Kit or device for detection of biliary tract cancer and detection method

Abstract

To provide a kit or device for detection of biliary tract cancer, and a detection method.SOLUTION: Provided is a kit for detection of biliary tract cancer, including a nucleic acid probe that specifically binds to a polynucleotide of miR-8069, a biliary tract cancer marker, or a precursor thereof, and / or a primer that specifically recognizes and amplifies the polynucleotide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a specific method for detecting the presence or absence of biliary tract cancer in a subject. A kit or device for detecting biliary tract cancer, which comprises a nucleic acid capable of specifically binding to miRNA, and A method for detecting biliary tract cancer, which includes measuring the expression level of the miRNA using the nucleic acid. do. [Background technology]

[0002] The biliary tract refers to the entire excretory pathway from bile secreted from hepatocytes to the duodenum. The extrahepatic biliary system is divided into the intrahepatic bile duct, which runs from the liver to the duodenum, and the extrahepatic biliary system, which runs from the liver to the duodenum. The extrahepatic bile duct, which exports bile, the gallbladder and bile duct, which temporarily store and concentrate bile, and the main pancreatic duct It is broadly divided into three parts: the duodenal papilla, which is the site that opens into the duodenal lumen, or the duodenal papilla.

[0003] Most biliary tract cancers are caused by the transformation of bile duct epithelial cells that line the lumen, and are treated with chemotherapy and radiation. Radiation therapy is ineffective, and early detection and surgical removal is the only definitive treatment. Biliary tract cancer does not have any noticeable symptoms. For example, if the cancer progresses and the bile duct becomes blocked, bile may flow back into the blood vessels. Since the first symptoms of cancer are jaundice and itching, it is often discovered at an advanced stage. Intrahepatic bile duct cancer rarely obstructs the extrahepatic bile duct, so in most cases The disease progresses without any symptoms of jaundice. Cancer deaths by site in Japan in 2011, as disclosed by the Cancer Control Information Center According to the statistics, the number of deaths from biliary tract cancer was 18,186, and The 5-year relative survival rate for cancer by site is 22.5% for men and 19.9% ​​for women, the second worst after pancreatic cancer. Because the biliary tract is closely connected to important organs such as the liver and pancreas, This is a factor that leads to metastasis and worsens the prognosis.

[0004] Biliary tract cancer is broadly divided into three types depending on the location of the cancer: extrahepatic bile duct cancer, gallbladder cancer, and ampullary cancer. Furthermore, extrahepatic bile duct cancer can occur in the hepatic hilum at the entrance to the liver (hilar bile duct cancer), or in the area extending from the hepatic hilum to the gallbladder. upper bile duct cancer, from the gallbladder to the pancreas (mid-bile duct cancer), and from the pancreas to the 12th Cancer occurring in the bile duct close to the liver is divided into four types: It is known that surgery is difficult and the prognosis is poor.

[0005] UICC(Unio Internationalis Contra Cancru) The progression of extrahepatic bile duct cancer, gallbladder cancer, and ampullary cancer according to the "Biliary Tract Cancer Treatment Guidelines, Article 5" (Edited by the Japanese Society of Biliary Surgery, Kanehara Publishing Co., Ltd., 2003, p. 109) The stage is determined by lymph node metastasis, extraperitoneal distant metastasis to other organs, and macroscopic extent of spread around the bile duct. They are classified into 0, IA, IB, IIA, IIB, III, IVa, and IVb. The progression of intrahepatic bile duct cancer is determined by the TNM Classification of Malignant Tumors, 7th Edition, Japanese Version (UICC Japan Committee, TNM Committee translation, Kanehara Publishing Co., Ltd., 2012, p. 110) The stage is determined by lymph node metastasis, extraperitoneal distant metastasis to other organs, and macroscopic extent of spread around the bile duct. They are classified into Di I, II, III, IVa, and IVb.

[0006] The initial diagnosis of biliary tract cancer generally involves minimally invasive blood biochemistry tests, tumor marker tests, and and abdominal ultrasound examination are used (Non-patent document 1). Blood biochemistry tests for detecting biliary tract cancer For example, alkaline phosphatase, γ-GTP, and bilirubin, which increase with liver dysfunction, Tumor markers for detecting biliary tract cancer include, for example, CEA and CA19. -9, DUPAN-2, CA195, CA242, IL-6, etc. are known. The way to use tumor markers is to check whether their blood concentration is higher than a predetermined reference value or If the CEA level is low, cancer is suspected. For example, as described in Non-Patent Document 2, The standard value is 5ng / mL, and the standard value for CA19-9 is 37U / mL. If this value is present, cancer, including biliary tract cancer, is suspected.

[0007] Although still in the research stage, the expression of proteins and genes in biological samples such as blood There have been reports of detecting biliary tract cancer using ionizing radiation.

[0008] Patent Document 1 describes a method for detecting biliary tract cancer using the expression level of proteins in biliary tract tissue. It is written.

[0009] In Patent Document 2, mRNA genes extracted from cells in the blood (monocytes, etc.) are used. Methods for diagnosing gastrointestinal cancers, including biliary tract cancer, are described. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japanese Patent Application Laid-Open No. 2012-237685 [Patent Document 2] Japanese Patent Application Laid-Open No. 2013-223520 [Non-patent literature]

[0011] [Non-Patent Document 1] Biliary Tract Cancer Treatment Guidelines Editorial Committee, "Evidence-Based Biliary Tract Cancer Treatment Guidelines," Igaku Tosho Publishing Co., Ltd., 2007, pp. 38-39 [Non-patent document 2] Kiyoshi Kurokawa, Clinical Laboratory Data Book, 2013, p. 633, 636 Summary of the Invention [Problem to be solved by the invention]

[0012] The object of the present invention is to discover a novel tumor marker for biliary tract cancer and to develop a compound that specifically binds to the marker. The object of the present invention is to provide a method for effectively detecting biliary tract cancer using nucleic acids that can be used. As described in Reference 1, the initial diagnosis of biliary tract cancer is generally performed using minimally invasive blood biochemistry tests. Abdominal ultrasound examinations are used to detect biliary tract cancer. The tumor imaging rate (the probability that cancer can be detected by imaging) ranges from 21 to 90% (Non-patent Document 1). This can lead to a decrease in the detection rate, especially when the cancer is located in the lower bile duct. For example, alkaline phosphatase, γ-GTP, and bilirubin, which increase with liver dysfunction, These blood biochemistry tests are also used to detect biliary tract cancer, but they do not specifically detect biliary tract cancer. In addition, tumor markers for detecting biliary tract cancer, such as CEA and C Known examples include A19-9, DUPAN-2, CA195, CA242, and IL-6. Of these, CEA is elevated in 40-70% of biliary tract cancer patients, and CA19-9 is elevated in 50- It is known that the level is elevated in 79% of biliary tract cancer patients (Non-patent Document 1), but It is not unusual, and Non-Patent Document 1 states that it is difficult to use for early diagnosis. In addition, DUPAN-2, CA195, CA242, and IL-6 are non-patented. Reference 1 states that its clinical usefulness is unclear. When conventional tumor markers are used, other cancers and / or biliary and / or peri-biliary organs There is also a possibility that benign tumors and / or diseases of the organs may be falsely detected.

[0013] Although still in the research stage, the expression of proteins and genes in biological samples such as blood There are reports on detecting biliary tract cancer using the current dose as shown below, but none of them have been put into practical use. That's not the case.

[0014] Patent Document 1 describes a method for detecting biliary tract cancer using the expression level of proteins in biliary tract tissue. However, this detection method requires surgical tissue sectioning to obtain specimens. This is a physically demanding process for the patient, and is therefore not a preferred testing method. In addition, Patent Document 1 does not provide a specific accuracy for distinguishing biliary tract cancer with regard to this detection method. There is no description of detection performance such as sensitivity and specificity, and the method lacks industrial practicality.

[0015] In Patent Document 2, mRNA genes extracted from cells in the blood (monocytes, etc.) are used. A method for diagnosing gastrointestinal cancer, including biliary tract cancer, has been described. It is necessary to use a combination of tens to hundreds of mRNAs, and it has not yet been developed as a test. If this occurs, there are concerns about increased testing costs and the complexity of the discrimination algorithm. A is considered to be unstable and easily decomposed in blood, so it is not a desirable test subject. stomach.

[0016] Thus, existing tumor markers have poor performance in detecting biliary tract cancer, or The performance and detection methods of research-stage markers have not been specifically described, so these When using this method, unnecessary additional testing can be avoided by misidentifying healthy subjects as biliary tract cancer patients. There is a possibility that treatment opportunities may be missed due to overlooking the treatment or overlooking biliary tract cancer patients. Measuring genes consisting of tens to hundreds of genes increases the cost of testing, so It is difficult to use for such large-scale screening. Since collecting biliary tissue is highly invasive to patients and undesirable, we have developed a method to collect biliary tissue in a minimally invasive manner. It is possible to detect the disease from blood, and to accurately distinguish biliary tract cancer patients from healthy individuals. A highly accurate marker for biliary tract cancer that can be distinguished is required. Since surgical resection is the only curative treatment, highly sensitive markers for biliary tract cancer are highly desired. [Means for solving the problem]

[0017] As a result of intensive research to solve the above problems, the present inventors have discovered a method for collecting biliary tract tissue from blood that can be collected minimally invasively. We have identified several genes that can be used as cancer detection markers, and have identified nucleic acids that can specifically bind to these genes. By using the above method, it was found that biliary tract cancer can be significantly detected, and the present invention was completed. I arrived.

[0018] <Summary of the Invention> That is, the present invention has the following features. (1) Biliary tract cancer markers: miR-125a-3p, miR-6893-5p, and iR-204-3p, miR-4476, miR-4294, miR-150-3p, m iR-6729-5p, miR-7641, miR-6765-3p, miR-6820 -5p, miR-575, miR-6836-3p, miR-1469, miR-663 a、miR-6075、miR-4634、miR-423-5p、miR-4454、 miR-7109-5p、miR-6789-5p、miR-6877-5p、miR- 4792、miR-4530、miR-7975、miR-6724-5p、miR-8 073、miR-7977、miR-1231、miR-6799-5p、miR-61 5-5p、miR-4450、miR-6726-5p、miR-6875-5p、mi R-4734, miR-16-5p, miR-602, miR-4651, miR-80 69、miR-1238-5p、miR-6880-5p、miR-8072、miR- 4723-5p、miR-4732-5p、miR-6125、miR-6090、mi R-7114-5p、miR-564、miR-451a、miR-3135b、miR -4497、miR-4665-5p、miR-3622a-5p、miR-6850- 5p、miR-6821-5p、miR-5100、miR-6872-3p、miR- 4433-3p、miR-1227-5p、miR-3188、miR-7704、mi R-3185、miR-1908-3p、miR-6781-5p、miR-6805- 5p、miR-8089、miR-665、miR-4486、miR-6722-3p miR-1260a, miR-4707-5p, miR-6741-5p, miR-1 260b、miR-1246、miR-6845-5p、miR-4638-5p、mi R-6085、miR-1228-3p、miR-4534、miR-5585-3p、 miR-4741, miR-4433b-3p, miR-197-5p, miR-718 , miR-4513, miR-4446-3p, miR-619-5p, miR-681 6-5p, miR-6778-5p, miR-24-3p, miR-1915-3p, m iR-4665-3p, miR-4449, miR-6889-5p, miR-486- 3p, miR-7113-3p, miR-642a-3p, miR-7847-3p, m iR-6768-5p, miR-1290, miR-7108-5p, miR-92b- 5p, miR-663b, miR-3940-5p, miR-4467, miR-685 8-5p, miR-4417, miR-3665, miR-4736, miR-4687 -3p, miR-1908-5p, miR-5195-3p, miR-4286, miR -3679-3p, miR-6791-5p, miR-1202, miR-3656, m iR-4746-3p, miR-3184-5p, miR-3937, miR-6515 -3p, miR-6132, miR-187-5p, miR-7111-5p, miR- 5787, miR-6779-5p, miR-4516, miR-4649-5p, mi R-760, miR-3162-5p, miR-3178, miR-940, miR-4 271, miR-6769b-5p, miR-4508, miR-6826-5p, mi From the group consisting of miR-6757-5p, miR-3131, and miR-1343-3p a nucleic acid capable of specifically binding to at least one selected polynucleotide; A kit for detecting road cancer.

[0019] (2) miR-125a-3p is hsa-miR-125a-3p and miR-68 93-5p is hsa-miR-6893-5p, and miR-204-3p is hsa- miR-204-3p, miR-4476 is hsa-miR-4476, and m iR-4294 is hsa-miR-4294, and miR-150-3p is hsa-m iR-150-3p and miR-6729-5p are hsa-miR-6729-5p , miR-7641 is hsa-miR-7641, and miR-6765-3p is hsa-miR-6765-3p, and miR-6820-5p is hsa-miR- 6820-5p, miR-575 is hsa-miR-575, and miR-68 36-3p is hsa-miR-6836-3p, and miR-1469 is hsa-mi miR-1469, miR-663a is hsa-miR-663a, and miR-6 075 is hsa-miR-6075, and miR-4634 is hsa-miR-463 4, miR-423-5p is hsa-miR-423-5p, and miR-44 54 is hsa-miR-4454, and miR-7109-5p is hsa-miR-7 109-5p, miR-6789-5p is hsa-miR-6789-5p , miR-6877-5p is hsa-miR-6877-5p, and miR-4792 is hsa-miR-4792 and miR-4530 is hsa-miR-4530 miR-7975 is hsa-miR-7975, and miR-6724-5p is hsa-miR-7975. sa-miR-6724-5p and miR-8073 is hsa-miR-8073 miR-7977 is hsa-miR-7977, and miR-1231 is hsa -miR-1231 and miR-6799-5p is hsa-miR-6799-5p , miR-615-5p is hsa-miR-615-5p, and miR-445 0 is hsa-miR-4450 and miR-6726-5p is hsa-miR-67 26-5p, and miR-6875-5p is hsa-miR-6875-5p; miR-4734 is hsa-miR-4734 and miR-16-5p is hsa-m iR-16-5p, miR-602 is hsa-miR-602, and miR-4 651 is hsa-miR-4651, and miR-8069 is hsa-miR-806 9, miR-1238-5p is hsa-miR-1238-5p, and miR- 6880-5p is hsa-miR-6880-5p, and miR-8072 is hsa- miR-8072 and miR-4723-5p are hsa-miR-4723-5p. miR-4732-5p is hsa-miR-4732-5p, and miR-61 25 is hsa-miR-6125 and miR-6090 is hsa-miR-6090 and miR-7114-5p is hsa-miR-7114-5p and miR-5 64 is hsa-miR-564, and miR-451a is hsa-miR-451a miR-3135b is hsa-miR-3135b, and miR-4497 is h sa-miR-4497 and miR-4665-5p is hsa-miR-4665- 5p, miR-3622a-5p is hsa-miR-3622a-5p, and m iR-6850-5p is hsa-miR-6850-5p and miR-6821-5 p is hsa-miR-6821-5p, and miR-5100 is hsa-miR-51 00, miR-6872-3p is hsa-miR-6872-3p, and miR -4433-3p is hsa-miR-4433-3p, and miR-1227-5p is hsa-miR-1227-5p and miR-3188 , miR-7704 is hsa-miR-7704, and miR-3185 is hs a-miR-3185 and miR-1908-3p is hsa-miR-1908-3 p, miR-6781-5p is hsa-miR-6781-5p, and miR- 6805-5p is hsa-miR-6805-5p, and miR-8089 is hsa- miR-8089, miR-665 is hsa-miR-665, and miR-4 486 is hsa-miR-4486, and miR-6722-3p is hsa-miR- 6722-3p, miR-1260a is hsa-miR-1260a, and mi R-4707-5p is hsa-miR-4707-5p, and miR-6741-5p is hsa-miR-6741-5p, and miR-1260b is hsa-miR-12 60b, miR-1246 is hsa-miR-1246, and miR-6845 -5p is hsa-miR-6845-5p, and miR-4638-5p is hsa-m iR-4638-5p, miR-6085 is hsa-miR-6085, and m iR-1228-3p is hsa-miR-1228-3p, and miR-4534 is h sa-miR-4534 and miR-5585-3p is hsa-miR-5585- 3p, miR-4741 is hsa-miR-4741, and miR-4433b -3p is hsa-miR-4433b-3p, and miR-197-5p is hsa-m iR-197-5p, miR-718 is hsa-miR-718, and miR- 4513 is hsa-miR-4513, and miR-4446-3p is hsa-miR -4446-3p, and miR-619-5p is hsa-miR-619-5p , miR-6816-5p is hsa-miR-6816-5p, and miR-6778 -5p is hsa-miR-6778-5p, and miR-24-3p is hsa-miR -24-3p, and miR-1915-3p is hsa-miR-1915-3p , miR-4665-3p is hsa-miR-4665-3p, and miR-4449 is hsa-miR-4449 and miR-6889-5p is hsa-miR-688 9-5p, miR-486-3p is hsa-miR-486-3p, and miR -7113-3p is hsa-miR-7113-3p, and miR-642a-3p is hsa-miR-642a-3p and miR-7847-3p are hsa-miR-7 847-3p, and miR-6768-5p is hsa-miR-6768-5p , miR-1290 is hsa-miR-1290, and miR-7108-5p is hs a-miR-7108-5p and miR-92b-5p is hsa-miR-92b- 5p, miR-663b is hsa-miR-663b, and miR-3940- 5p is hsa-miR-3940-5p, and miR-4467 is hsa-miR-4 467, miR-6858-5p is hsa-miR-6858-5p, and mi R-4417 is hsa-miR-4417, and miR-3665 is hsa-miR- 3665, miR-4736 is hsa-miR-4736, and miR-468 7-3p is hsa-miR-4687-3p, and miR-1908-5p is hsa- miR-1908-5p and miR-5195-3p are hsa-miR-5195- 3p, miR-4286 is hsa-miR-4286, and miR-3679- 3p is hsa-miR-3679-3p, and miR-6791-5p is hsa-mi miR-6791-5p, miR-1202 is hsa-miR-1202, and mi R-3656 is hsa-miR-3656, and miR-4746-3p is hsa-m iR-4746-3p and miR-3184-5p are hsa-miR-3184-5 p, miR-3937 is hsa-miR-3937, and miR-6515-3 p is hsa-miR-6515-3p, and miR-6132 is hsa-miR-61 32, miR-187-5p is hsa-miR-187-5p, and miR-7 111-5p is hsa-miR-7111-5p, and miR-5787 is hsa-m iR-5787 and miR-6779-5p are hsa-miR-6779-5 p, miR-4516 is hsa-miR-4516, and miR-4649-5 p is hsa-miR-4649-5p and miR-760 is hsa-miR-760 , miR-3162-5p is hsa-miR-3162-5p, and miR-3 178 is hsa-miR-3178, and miR-940 is hsa-miR-940. miR-4271 is hsa-miR-4271, and miR-6769b-5p is hsa-miR-6769b-5p, and miR-4508 is hsa-miR-45 08, miR-6826-5p is hsa-miR-6826-5p, and miR -6757-5p is hsa-miR-6757-5p, and miR-3131 is hsa -miR-3131, and miR-1343-3p is hsa-miR-1343 The kit according to (1), wherein the kit is -3p.

[0020] (3) The nucleic acid is a polynucleotide shown in (a) to (e) below: (a) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or Polynucleotides consisting of a base sequence in which u is replaced by t, their variants, and derivatives thereof a conductor or a fragment thereof containing 15 or more consecutive bases, (b) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478; cleotide, (c) a base sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or a polynucleotide consisting of a base sequence complementary to a base sequence in which u is replaced by t; a variant thereof, a derivative thereof, or a fragment thereof containing 15 or more consecutive bases; (d) a base sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or A polynucleotide containing a base sequence complementary to the base sequence in which u is t, and Beauty (e) A polynucleotide that binds to any one of the polynucleotides (a) to (d) under stringent conditions. hybridizing polynucleotides, The kit according to (1) or (2), wherein the polynucleotide is selected from the group consisting of:

[0021] (4) The kit further comprises another biliary tract cancer marker, miR-6808-5p, miR- 6774-5p, miR-4656, miR-6806-5p, miR-1233-5p , miR-328-5p, miR-4674, miR-2110, miR-6076, m iR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR -638, miR-2861, miR-371a-5p, miR-211-3p, miR -1273g-3p, miR-1203, miR-122-5p, miR-4258, m iR-4484, miR-4648, and miR-6780b-5p (The nucleic acid further comprises a nucleic acid capable of specifically binding to at least one or more polynucleotides selected from the group consisting of: The kit according to any one of 1) to (3).

[0022] (5) miR-6808-5p is hsa-miR-6808-5p and miR-67 74-5p is hsa-miR-6774-5p, and miR-4656 is hsa-mi R-4656, and miR-6806-5p is hsa-miR-6806-5p , miR-1233-5p is hsa-miR-1233-5p, and miR-328- 5p is hsa-miR-328-5p, and miR-4674 is hsa-miR-46 74, miR-2110 is hsa-miR-2110, and miR-6076 is hsa-miR-6076 and miR-3619-3p are hsa-miR-3619 -3p, and miR-92a-2-5p is hsa-miR-92a-2-5p; miR-128-1-5p is hsa-miR-128-1-5p, and miR-638 is hsa-miR-638 and miR-2861 is hsa-miR-2861 , miR-371a-5p is hsa-miR-371a-5p, and miR-211- 3p is hsa-miR-211-3p, and miR-1273g-3p is hsa-mi R-1273g-3p, miR-1203 is hsa-miR-1203, and m iR-122-5p is hsa-miR-122-5p, and miR-4258 is hsa -miR-4258, miR-4484 is hsa-miR-4484, and mi R-4648 is hsa-miR-4648, and miR-6780b-5p is h The kit according to (4), wherein the miR-6780b-5p is sa-miR-6780b-5p.

[0023] (6) The nucleic acid is a polynucleotide shown in (f) to (j) below: (f) a base sequence represented by any one of SEQ ID NOs: 126 to 148 or the base sequence a polynucleotide consisting of a base sequence in which u is t, a variant thereof, a derivative thereof, or a fragment thereof containing 5 or more consecutive bases; (g) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 126 to 148; (h) a base sequence represented by any one of SEQ ID NOs: 126 to 148 or the base sequence a polynucleotide consisting of a base sequence complementary to the base sequence in which u is t, a variant thereof, its derivatives or fragments containing 15 or more consecutive bases; (i) a base sequence represented by any one of SEQ ID NOs: 126 to 148 or the base sequence a polynucleotide comprising a base sequence complementary to the base sequence in which u is t; (j) A method for detecting a polynucleotide that is hybridized with any one of the polynucleotides (f) to (i) under stringent conditions. hybridizing polynucleotides, The kit according to (4) or (5), wherein the polynucleotide is selected from the group consisting of:

[0024] (7) The kit includes a biliary tract cancer marker selected from all of the biliary tract cancer markers described in (1) or (2). At least two polynucleotides capable of specifically binding to each of the at least two or more polynucleotides The kit according to any one of (1) to (6), comprising one or more nucleic acids.

[0025] (8) Biliary tract cancer markers: miR-125a-3p, miR-6893-5p, and miR- iR-204-3p, miR-4476, miR-4294, miR-150-3p, m iR-6729-5p, miR-7641, miR-6765-3p, miR-6820 -5p, miR-575, miR-6836-3p, miR-1469, miR-663 a, miR-6075, miR-4634, miR-423-5p, miR-4454, miR-7109-5p, miR-6789-5p, miR-6877-5p, miR- 4792, miR-4530, miR-7975, miR-6724-5p, miR-8 073, miR-7977, miR-1231, miR-6799-5p, miR-61 5-5p, miR-4450, miR-6726-5p, miR-6875-5p, mi R-4734, miR-16-5p, miR-602, miR-4651, miR-80 69, miR-1238-5p, miR-6880-5p, miR-8072, miR- 4723-5p, miR-4732-5p, miR-6125, miR-6090, mi R-7114-5p, miR-564, miR-451a, miR-3135b, miR -4497, miR-4665-5p, miR-3622a-5p, miR-6850- 5p, miR-6821-5p, miR-5100, miR-6872-3p, miR- 4433-3p、miR-1227-5p、miR-3188、miR-7704、mi R-3185、miR-1908-3p、miR-6781-5p、miR-6805- 5p、miR-8089、miR-665、miR-4486、miR-6722-3p miR-1260a, miR-4707-5p, miR-6741-5p, miR-1 260b、miR-1246、miR-6845-5p、miR-4638-5p、mi R-6085、miR-1228-3p、miR-4534、miR-5585-3p、 miR-4741, miR-4433b-3p, miR-197-5p, miR-718 miR-4513, miR-4446-3p, miR-619-5p, miR-681 6-5p、miR-6778-5p、miR-24-3p、miR-1915-3p、m iR-4665-3p、miR-4449、miR-6889-5p、miR-486- 3p、miR-7113-3p、miR-642a-3p、miR-7847-3p、m iR-6768-5p、miR-1290、miR-7108-5p、miR-92b- 5p、miR-663b、miR-3940-5p、miR-4467、miR-685 8-5p、miR-4417、miR-3665、miR-4736、miR-4687 -3p、miR-1908-5p、miR-5195-3p、miR-4286、miR -3679-3p、miR-6791-5p、miR-1202、miR-3656、m iR-4746-3p、miR-3184-5p、miR-3937、miR-6515 -3p、miR-6132、miR-187-5p、miR-7111-5p、miR- 5787、miR-6779-5p、miR-4516、miR-4649-5p、mi R-760, miR-3162-5p, miR-3178, miR-940, miR-4 271, miR-6769b-5p, miR-4508, miR-6826-5p, mi From the group consisting of miR-6757-5p, miR-3131, and miR-1343-3p a nucleic acid capable of specifically binding to at least one selected polynucleotide; A device for detecting road cancer.

[0026] (9) miR-125a-3p is hsa-miR-125a-3p, and miR-68 93-5p is hsa-miR-6893-5p, and miR-204-3p is hsa- miR-204-3p, miR-4476 is hsa-miR-4476, and m iR-4294 is hsa-miR-4294, and miR-150-3p is hsa-m iR-150-3p and miR-6729-5p are hsa-miR-6729-5p , miR-7641 is hsa-miR-7641, and miR-6765-3p is hsa-miR-6765-3p, and miR-6820-5p is hsa-miR- 6820-5p, miR-575 is hsa-miR-575, and miR-68 36-3p is hsa-miR-6836-3p, and miR-1469 is hsa-mi miR-1469, miR-663a is hsa-miR-663a, and miR-6 075 is hsa-miR-6075, and miR-4634 is hsa-miR-463 4, miR-423-5p is hsa-miR-423-5p, and miR-44 54 is hsa-miR-4454, and miR-7109-5p is hsa-miR-7 109-5p, miR-6789-5p is hsa-miR-6789-5p , miR-6877-5p is hsa-miR-6877-5p, and miR-4792 is hsa-miR-4792 and miR-4530 is hsa-miR-4530 miR-7975 is hsa-miR-7975, and miR-6724-5p is hsa-miR-7975. sa-miR-6724-5p and miR-8073 is hsa-miR-8073 miR-7977 is hsa-miR-7977, and miR-1231 is hsa -miR-1231 and miR-6799-5p is hsa-miR-6799-5p , miR-615-5p is hsa-miR-615-5p, and miR-445 0 is hsa-miR-4450 and miR-6726-5p is hsa-miR-67 26-5p, and miR-6875-5p is hsa-miR-6875-5p; miR-4734 is hsa-miR-4734 and miR-16-5p is hsa-m iR-16-5p, miR-602 is hsa-miR-602, and miR-4 651 is hsa-miR-4651, and miR-8069 is hsa-miR-806 9, miR-1238-5p is hsa-miR-1238-5p, and miR- 6880-5p is hsa-miR-6880-5p, and miR-8072 is hsa- miR-8072 and miR-4723-5p are hsa-miR-4723-5p. miR-4732-5p is hsa-miR-4732-5p, and miR-61 25 is hsa-miR-6125 and miR-6090 is hsa-miR-6090 and miR-7114-5p is hsa-miR-7114-5p and miR-5 64 is hsa-miR-564, and miR-451a is hsa-miR-451a miR-3135b is hsa-miR-3135b, and miR-4497 is h sa-miR-4497 and miR-4665-5p is hsa-miR-4665- 5p, miR-3622a-5p is hsa-miR-3622a-5p, and m iR-6850-5p is hsa-miR-6850-5p and miR-6821-5 p is hsa-miR-6821-5p, and miR-5100 is hsa-miR-51 00, miR-6872-3p is hsa-miR-6872-3p, and miR -4433-3p is hsa-miR-4433-3p, and miR-1227-5p is hsa-miR-1227-5p and miR-3188 , miR-7704 is hsa-miR-7704, and miR-3185 is hs a-miR-3185 and miR-1908-3p is hsa-miR-1908-3 p, miR-6781-5p is hsa-miR-6781-5p, and miR- 6805-5p is hsa-miR-6805-5p, and miR-8089 is hsa- miR-8089, miR-665 is hsa-miR-665, and miR-4 486 is hsa-miR-4486, and miR-6722-3p is hsa-miR- 6722-3p, miR-1260a is hsa-miR-1260a, and mi R-4707-5p is hsa-miR-4707-5p, and miR-6741-5p is hsa-miR-6741-5p, and miR-1260b is hsa-miR-12 60b, miR-1246 is hsa-miR-1246, and miR-6845 -5p is hsa-miR-6845-5p, and miR-4638-5p is hsa-m iR-4638-5p, miR-6085 is hsa-miR-6085, and m iR-1228-3p is hsa-miR-1228-3p, and miR-4534 is h sa-miR-4534 and miR-5585-3p is hsa-miR-5585- 3p, miR-4741 is hsa-miR-4741, and miR-4433b -3p is hsa-miR-4433b-3p, and miR-197-5p is hsa-m iR-197-5p, miR-718 is hsa-miR-718, and miR- 4513 is hsa-miR-4513, and miR-4446-3p is hsa-miR -4446-3p, and miR-619-5p is hsa-miR-619-5p , miR-6816-5p is hsa-miR-6816-5p, and miR-6778 -5p is hsa-miR-6778-5p, and miR-24-3p is hsa-miR -24-3p, and miR-1915-3p is hsa-miR-1915-3p , miR-4665-3p is hsa-miR-4665-3p, and miR-4449 is hsa-miR-4449 and miR-6889-5p is hsa-miR-688 9-5p, miR-486-3p is hsa-miR-486-3p, and miR -7113-3p is hsa-miR-7113-3p, and miR-642a-3p is hsa-miR-642a-3p and miR-7847-3p are hsa-miR-7 847-3p, and miR-6768-5p is hsa-miR-6768-5p , miR-1290 is hsa-miR-1290, and miR-7108-5p is hs a-miR-7108-5p and miR-92b-5p is hsa-miR-92b- 5p, miR-663b is hsa-miR-663b, and miR-3940- 5p is hsa-miR-3940-5p, and miR-4467 is hsa-miR-4 467, miR-6858-5p is hsa-miR-6858-5p, and mi R-4417 is hsa-miR-4417, and miR-3665 is hsa-miR- 3665, miR-4736 is hsa-miR-4736, and miR-468 7-3p is hsa-miR-4687-3p, and miR-1908-5p is hsa- miR-1908-5p and miR-5195-3p are hsa-miR-5195- 3p, miR-4286 is hsa-miR-4286, and miR-3679- 3p is hsa-miR-3679-3p, and miR-6791-5p is hsa-mi miR-6791-5p, miR-1202 is hsa-miR-1202, and mi R-3656 is hsa-miR-3656, and miR-4746-3p is hsa-m iR-4746-3p and miR-3184-5p are hsa-miR-3184-5 p, miR-3937 is hsa-miR-3937, and miR-6515-3 p is hsa-miR-6515-3p, and miR-6132 is hsa-miR-61 32, miR-187-5p is hsa-miR-187-5p, and miR-7 111-5p is hsa-miR-7111-5p, and miR-5787 is hsa-m iR-5787 and miR-6779-5p are hsa-miR-6779-5 p, miR-4516 is hsa-miR-4516, and miR-4649-5 p is hsa-miR-4649-5p and miR-760 is hsa-miR-760 , miR-3162-5p is hsa-miR-3162-5p, and miR-3 178 is hsa-miR-3178, and miR-940 is hsa-miR-940. miR-4271 is hsa-miR-4271, and miR-6769b-5p is hsa-miR-6769b-5p, and miR-4508 is hsa-miR-45 08, miR-6826-5p is hsa-miR-6826-5p, and miR -6757-5p is hsa-miR-6757-5p, and miR-3131 is hsa -miR-3131, and miR-1343-3p is hsa-miR-1343 The device according to (8), wherein the device is -3p.

[0027] (10) The nucleic acid is a polynucleotide shown in any one of (a) to (e) below: (a) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide consisting of the base sequence in which u is replaced by t, a variant thereof, or a fragment thereof containing 15 or more consecutive bases, (b) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478; cleotide, (c) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding A polynucleotide consisting of a base sequence complementary to the base sequence in which u is t. a fragment thereof containing 15 or more consecutive bases, (d) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide comprising a base sequence complementary to the base sequence in which u is t , and (e) A polynucleotide that binds to any one of the polynucleotides (a) to (d) under stringent conditions. hybridizing polynucleotides, The device according to (8) or (9), wherein the polynucleotide is selected from the group consisting of .

[0028] (11) The device is capable of detecting another biliary tract cancer marker, miR-6808-5p, mi R-6774-5p, miR-4656, miR-6806-5p, miR-1233- 5p, miR-328-5p, miR-4674, miR-2110, miR-6076 , miR-3619-3p, miR-92a-2-5p, miR-128-1-5p, m iR-638, miR-2861, miR-371a-5p, miR-211-3p, m iR-1273g-3p, miR-1203, miR-122-5p, miR-4258 , miR-4484, miR-4648, and miR-6780b-5p The nucleic acid further comprises a nucleic acid capable of specifically binding to at least one or more polynucleotides selected. 2. The device according to any one of (8) to (10).

[0029] (12) miR-6808-5p is hsa-miR-6808-5p, and miR-6 774-5p is hsa-miR-6774-5p, and miR-4656 is hsa-m iR-4656 and miR-6806-5p is hsa-miR-6806-5p miR-1233-5p is hsa-miR-1233-5p, and miR-328 -5p is hsa-miR-328-5p, and miR-4674 is hsa-miR-4 674, miR-2110 is hsa-miR-2110, and miR-6076 is hsa-miR-6076 and miR-3619-3p is hsa-miR-361 9-3p, and miR-92a-2-5p is hsa-miR-92a-2-5p , miR-128-1-5p is hsa-miR-128-1-5p, and miR-63 8 is hsa-miR-638 and miR-2861 is hsa-miR-2861. miR-371a-5p is hsa-miR-371a-5p, and miR-211 -3p is hsa-miR-211-3p, and miR-1273g-3p is hsa-m iR-1273g-3p, miR-1203 is hsa-miR-1203, miR-122-5p is hsa-miR-122-5p and miR-4258 is hs a-miR-4258, miR-4484 is hsa-miR-4484, and m iR-4648 is hsa-miR-4648, and miR-6780b-5p is The device according to (11), wherein the miR-6780b-5p is hsa-miR-6780b-5p.

[0030] (13) The nucleic acid is a polynucleotide shown in (f) to (j) below: (f) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide consisting of the base sequence in which u is t, a variant thereof, a derivative thereof, or is a fragment containing 15 or more consecutive bases, (g) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 126 to 148; (h) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide consisting of a base sequence complementary to the base sequence in which u is t, and a variant thereof a fragment thereof containing 15 or more consecutive bases, (i) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide comprising a base sequence complementary to the base sequence in which u is t; and (j) A method for detecting a polynucleotide that is hybridized with any one of the polynucleotides (f) to (i) under stringent conditions. hybridizing polynucleotides, The device according to (11) or (12), which is a polynucleotide selected from the group consisting of Chair.

[0031] (14) The device is a device for measurement by hybridization technology. The device according to any one of (8) to (13). (15) The method according to (14), wherein the hybridization technique is a nucleic acid array technique. device. (16) The device is a marker selected from all of the biliary tract cancer markers described in (8) or (9). At least one polynucleotide capable of specifically binding to each of at least two or more polynucleotides to be The device according to any one of (8) to (15), comprising at least two nucleic acids.

[0032] (17) The kit according to any one of (1) to (7) or (8) to (16). The expression level of the target nucleic acid in a specimen of a subject is measured using the device described above, and the measured The expression level and the control expression level of a similarly measured healthy subject were used to determine whether the subject had biliary tract cancer. This includes in vitro assessment of whether or not a patient has biliary tract cancer. Hmm, a method for detecting biliary tract cancer. (18) The method according to (17), wherein the subject is a human. (19) The method according to (17) or (18), wherein the sample is blood, serum, or plasma.

[0033] <Terminology> Terms used herein have the following definitions.

[0034] As used herein, the term "biliary tract cancer" refers to any malignant tumor that forms in the biliary tract. Specifically, extrahepatic bile duct cancer, gallbladder cancer, ampullary cancer, duodenal ampullary cancer, and intrahepatic bile duct cancer This includes cancer.

[0035] As used herein, "benign tumors and / or benign diseases of the biliary tract and / or organs surrounding the biliary tract" means It refers to non-malignant tumors of the bile duct, liver, and pancreas.

[0036] Nucleotide, polynucleotide, DNA, RNA, etc. are abbreviated as "base sequence" Guidelines for the Preparation of Specifications Including Sequences or Amino Acid Sequences" (edited by the Japan Patent Office) and and conventions in the art shall be followed.

[0037] As used herein, the term "polynucleotide" refers to RNA, DNA, and RNA / DNA ( The term "DNA" refers to nucleic acids that include both cDNA and chimeric DNA. The above-mentioned RNA includes total DNA, genomic DNA, and synthetic DNA. l RNA, mRNA, rRNA, miRNA, siRNA, snoRNA, snRNA , including both non-coding RNA and synthetic RNA. As used herein, "synthetic DNA" and "synthetic RNA" refer to a DNA having a predetermined base sequence (natural sequence). or a non-natural sequence), using an automated nucleic acid synthesizer, for example. As used herein, the term "non-natural sequence" refers to DNA and RNA that have been artificially produced. and is intended to mean a sequence that differs from the native sequence, e.g., by one or more nucleotides. sequences containing substitutions, deletions, insertions and / or additions of one or more modified sequences (i.e., mutant sequences); The term "sequence" as used herein also encompasses sequences containing nucleotides (i.e., modified sequences), etc. Polynucleotide is used interchangeably with nucleic acid.

[0038] As used herein, the term "fragment" refers to a fragment having a continuous partial base sequence of a polynucleotide. It is a polynucleotide having 15 or more bases, preferably 17 or more bases, and more preferably 1 It is desirable that the length be 9 bases or more.

[0039] As used herein, the term "gene" refers not only to RNA and double-stranded DNA, but also to any of the components thereof. Each strand contains a single strand of DNA, such as the positive strand (or sense strand) or the complementary strand (or antisense strand). The term "subject matter" is intended to encompass all subjects, and is not particularly limited by its length.

[0040] Therefore, in this specification, unless otherwise specified, the term "gene" includes human genomic DNA. Double-stranded DNA, single-stranded DNA (positive strand), and single-stranded DNA with a sequence complementary to the positive strand (complementary strand, including cDNA), microRNA (miRNA), and their fragments, The term "gene" includes both a specific base sequence (or sequence number). Not only are the "genes" expressed, but the RNAs encoded by them and their biological functions are also Equivalent RNAs, e.g., homologs (i.e., homologs or orthologs), polynucleotides, The term "nucleic acid" includes "nucleic acids" that encode variants, such as homologs, variants, or derivatives. Specifically, the "nucleic acid" encoding the derivative is a nucleic acid that satisfies the stringent conditions described below. A nucleotide sequence represented by any one of SEQ ID NOs: 1 to 509, or a nucleotide sequence "nucleic acid" having a base sequence that hybridizes with a complementary sequence of the base sequence in which u is t "The term "gene" does not refer to any specific functional domain, and can be used to refer to any specific gene, even if it is a specific gene. For example, it may include an expression control region, a coding region, an exon, or an intron. The gene may be contained within the cell, or may be released outside the cell and exist independently. It may also be in a state encapsulated in a vesicle called an exosome.

[0041] As used herein, "exosomes" (also known as "exosomes") are molecules secreted from cells. Exosomes are small vesicles enclosed in a lipid bilayer membrane. They originate from multivesicular endosomes and are extracellular. When released into the environment, they lose internal biological substances such as genes (e.g., RNA and DNA) and proteins. Exosomes are found in bodily fluids such as blood, serum, plasma, and lymph. is known.

[0042] As used herein, the term "transcription product" refers to a RNA synthesized using the DNA sequence of a gene as a template. A refers to the region called the promoter upstream of the gene where RNA polymerase is located. and binds to the 3' end of the DNA, and binds a ribonucleotide to the 3' end so that it is complementary to the base sequence of the DNA. This RNA contains not only the gene itself but also the the region from the transcription start site to the poly(A) sequence, including the coding region, exon or intron The entire sequence is included, all the way to the termini.

[0043] In addition, in this specification, unless otherwise specified, "microRNA (miRNA)" means It is transcribed as a hairpin-like RNA precursor and has RNase III cleavage activity. It is cleaved by sRNA cleavage enzymes and incorporated into a protein complex called RISC, Non-coding RNAs of 15 to 25 bases involved in RNA translational repression are used intentionally. Furthermore, as used herein, "miRNA" is represented by a specific base sequence (or SEQ ID NO:). In addition to the miRNAs themselves, we also study the precursors of these miRNAs (pre-miRNAs, p ri-miRNAs), and miRNAs with equivalent biological functions, e.g., homologs (i.e., homologs or orthologs), variants such as genetic polymorphisms, and derivatives. Such precursors, homologues, variants or derivatives include, in particular, miRBas e release 20 (http: / / www.mirbase.org / ) and can identify the sequences of SEQ ID NOs: 1 to 509 under the stringent conditions described below. A base sequence that hybridizes with the complementary sequence of any specific base sequence represented by Furthermore, the term "miRNA" as used herein can be used to refer to a specific miRNA. The "miR" may be a gene product of a miR gene, and such a gene product is a mature miR. iRNA (for example, 15 to 25 bases involved in the translational repression of mRNA as described above, or 9-25 bases, non-coding RNA) or miRNA precursor (e.g., miRNAs (pre-miRNA or pri-miRNA).

[0044] As used herein, the term "probe" refers to RNA generated by gene expression or a probe derived therefrom. Polynucleotides and / or includes polynucleotides complementary thereto.

[0045] As used herein, the term "primer" refers to an RNA generated by gene expression or a primer therefor. A polynucleotide that specifically recognizes and amplifies the polynucleotide from which it is derived and / or The present invention encompasses polynucleotides complementary to the sequences of the sequences of the present invention.

[0046] Here, the complementary polynucleotide (complementary strand, reverse strand) is any one of SEQ ID NOs: 1 to 509. a base sequence defined by the above formula, or a base sequence in which u is t; The full-length sequence of a polynucleotide consisting of the above, or a partial sequence thereof (for convenience, this is referred to as the correct sequence here) base-complementary to the nucleotide sequence (called the "strand") based on base pairing relationships such as A:T(U) and G:C The term "complementary strand" refers to a polynucleotide that is in a complementary relationship to the target strand. It is not limited to cases where the base sequence is completely complementary to the target positive strand. The complementary relationship may be such that the hybridization occurs under certain conditions.

[0047] As used herein, "stringent conditions" refers to conditions under which a nucleic acid probe is highly sensitive to other sequences. to a greater extent than (e.g., the average of background measurements + the standard of background measurements) The conditions are those under which the hybridization occurs with respect to the target sequence with a standard error of at least 2 times the measured value. Stringent conditions are sequence-dependent and depend on the environment in which the hybridization occurs. The stringency of hybridization and / or washing conditions can be controlled. By doing so, target sequences that are 100% complementary to the nucleic acid probe can be identified. Specific examples of "stringent conditions" will be described later.

[0048] As used herein, the term "Tm value" refers to the time at which the double-stranded portion of a polynucleotide is denatured into a single strand. means the temperature at which double-stranded and single-stranded molecules exist in a 1:1 ratio.

[0049] As used herein, the term "variant" refers to a naturally occurring variant of a nucleic acid resulting from polymorphism, mutation, etc. or a variant thereof, or any of the base sequences of SEQ ID NOs: 1 to 509, or In the base sequence in which u is t, or in a partial sequence thereof, one or more bases are deleted or substituted. a mutant containing a substitution, addition or insertion, or a nucleotide sequence or a partial sequence thereof, and % or more, about 95% or more, about 97% or more, about 98% or more, or about 99% or more percent identity Variants, or polynucleotides or oligonucleotides containing the base sequence or a partial sequence thereof The term "nucleotide sequence" refers to a nucleic acid that hybridizes with a target nucleic acid under stringent conditions as defined above.

[0050] As used herein, "several" refers to an integer of about 10, 9, 8, 7, 6, 5, 4, 3, or 2. means.

[0051] As used herein, the term "mutant" refers to a mutation obtained by site-directed mutagenesis or PCR. They can be produced using well-known techniques such as heterotransferase.

[0052] As used herein, "% identity" refers to the percentage of identity between proteins or sequences as determined by BLAST or FASTA as described above. using a gene search system, with or without introducing gaps, can be determined (Zheng Zhang et al., 2000, J. Comput. Biol., vol. 7, pp. 203-214; Altschul, SF et al., 1990, Journal of Molecular Biology, Vol. 215, p. 403- 410; Pearson, W.R. et al., 1988, Proc. Natl. Acad. . Sci. USA, Vol. 85, p2444-2448).

[0053] As used herein, the term "derivative" refers to a modified nucleic acid, for example, but not limited to, labeling with a fluorophore or the like. modified nucleotides (e.g., halogenated, alkyl, such as methyl, methoxy, etc.); Reconstruction of nucleotides and bases containing alkoxy, thio, carboxymethyl, etc. groups nucleotides that have undergone double bond saturation, deamination, and substitution of oxygen molecules with sulfur molecules derivatives including PNA (peptide nucleic acid; Niel Sen, PE et al., 1991, Science, Vol. 254, pp. 1497-500) LNA (locked nucleic acid; Obika, S. et al., 1998) , Tetrahedron Lett., Vol. 39, p5401-5404) This means:

[0054] In the present specification, a polynucleotide selected from the group of miRNAs that are biliary tract cancer markers is The "nucleic acid" capable of specifically binding to a nucleotide is a synthetic or prepared nucleic acid, and The test contains a "nucleic acid probe" or "primer" and is used to detect the presence or absence of biliary tract cancer in a subject. To find out whether or not a patient has biliary tract cancer, the degree of the disease, and whether or not the patient has improved in biliary tract cancer. To diagnose the severity and sensitivity of biliary tract cancer to treatment, or to prevent or improve biliary tract cancer Alternatively, it may be used directly or indirectly to screen for candidate substances useful in therapy. These include the distribution of nucleotides in vivo, particularly in samples of body fluids such as blood and urine, in relation to the onset of biliary tract cancer. Specifically recognizes the transcription product represented by any of sequence numbers 1 to 509 or its cDNA synthetic nucleic acid. It includes nucleotides, oligonucleotides and polynucleotides that can recognize and bind to These nucleotides, oligonucleotides and polynucleotides have the above properties. and a probe for detecting the above gene expressed in vivo, in tissues, cells, etc., based on the above. and can be effectively used as a primer for amplifying the above genes expressed in vivo. It is possible.

[0055] The term "detection" as used herein means inspection, measurement, detection, or decision support. In addition, the term "evaluation" as used herein refers to test results or measurement results. It is used to include assisting in diagnosis or evaluation based on the above.

[0056] As used herein, a "subject" refers to a human, a primate, including a chimpanzee, a dog, a cat, or the like. Any pet animals, livestock animals such as cows, horses, sheep, goats, rodents such as mice and rats A "healthy individual" also refers to such a mammal, It means an animal that is not affected by the cancer to be detected.

[0057] As used herein, "P" or "P value" refers to the probability that a statistical test will yield a positive result under the null hypothesis. indicates the probability that a statistic more extreme than the statistic calculated from the actual data will be observed. Therefore, the smaller the "P" or "P value," the more significant the difference between the compared subjects.

[0058] As used herein, "sensitivity" refers to the value of (the number of true positives) / (the number of true positives + the number of false negatives). High sensitivity makes it possible to detect biliary tract cancer early and to identify the complete cancer site. This leads to a reduction in resection and recurrence rates.

[0059] As used herein, "specificity" means (number of true negatives) / (number of true negatives + number of false positives). If the specificity is high, unnecessary additional testing due to misclassification of healthy subjects as biliary tract cancer patients will be avoided. This will prevent the implementation of the procedure, reducing the burden on patients and cutting medical costs.

[0060] In this specification, "accuracy" means the value of (number of true positives + number of true negatives) / (total number of cases). Accuracy indicates the percentage of all samples for which the discrimination results were correct, and is used to evaluate detection performance. This will be the first indicator.

[0061] In this specification, the term "specimen" as a target for determination, detection or diagnosis refers to a substance that is capable of detecting the occurrence of biliary tract cancer, ... or the like. The expression of the gene of the present invention changes with the progression of biliary tract cancer and the therapeutic effect on biliary tract cancer. Specifically, it refers to biliary tissue and its surrounding blood vessels, lymph nodes, and Organs, organs suspected of metastasis, skin, and bodily fluids such as blood, urine, saliva, sweat, and tissue exudates This refers to serum and plasma prepared from blood, as well as feces, hair, etc. This refers to biological samples collected from the body, specifically genes such as RNA and miRNA.

[0062] As used herein, "hsa-miR-125a-3p gene" or "hsa-mi The term "miR-125a-3p" refers to hsa-miR-125a-3p as set forth in SEQ ID NO: 1. p gene (miRBase Accession No. MIMAT0004602) It also includes homologs or orthologs from other species. The 3p genes are described in Lagos-Quintana M et al., 2002, Curr Biol. It can be obtained by the method described in Vol. 12, pp. 735-739. -miR-125a-3p has a hairpin-like structure as its precursor, "hsa-mi r-125a” (miRBase Accession No. MI0000469, Column number 149) is known.

[0063] As used herein, "hsa-miR-6893-5p gene" or "hsa-mi The term "miR-6893-5p" refers to hsa-miR-6893-5p as set forth in SEQ ID NO: 2. p gene (miRBase Accession No. MIMAT0027686) It also includes homologs or orthologs from other species. The 5p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. 1 The "hsa-miR" can be obtained by the method described in JP-A-2004-1634-1645. -6893-5p is a precursor of hsa-mir-68, which has a hairpin-like structure. 93" (miRBase Accession No. MI0022740, SEQ ID NO: 1 50) is known.

[0064] As used herein, "hsa-miR-204-3p gene" or "hsa-miR The term "miR-204-3p" refers to the hsa-miR-204-3p gene set forth in SEQ ID NO: 3. miRBase Accession No. MIMAT0022693 and others Includes species homologs or orthologs. hsa-miR-204-3p gene The child is described in Lim LP et al., 2003, Science, Vol. 299, p. 1540. In addition, "hsa-miR-204-3p" can be obtained by the method The miRBase Accelerator, "hsa-mir-204" (miRBase Accelerator), has a hairpin-like structure. Session No. MI0000284, SEQ ID NO: 151) is known.

[0065] As used herein, "hsa-miR-4476 gene" or "hsa-miR-4 The term "miR-4476" refers to the hsa-miR-4476 gene (miRB) set forth in SEQ ID NO: 4. ase Accession No. MIMAT0019003) and other species homologues The hsa-miR-4476 gene is a member of the Jima According to the method described in DD et al., 2010, Blood, Vol. 116, p. e118-e127 In addition, "hsa-miR-4476" can be obtained by The pin-like structure of "hsa-mir-4476" (miRBase Accession No. No. MI0016828, SEQ ID NO: 152) are known.

[0066] As used herein, "hsa-miR-4294 gene" or "hsa-miR-4 The term "miR-4294" refers to the hsa-miR-4294 gene (miRB294) set forth in SEQ ID NO: 5. ase Accession No. MIMAT0016849) and other species homologues The hsa-miR-4294 gene is a member of the Goff obtained by the method described in LA et al., 2009, PLoS One, Vol. 4, e7192 In addition, "hsa-miR-4294" has a hairpin-like structure as its precursor. The structure of "hsa-mir-4294" (miRBase Accession No. .MI0015827, sequence number 153) is known.

[0067] As used herein, "hsa-miR-150-3p gene" or "hsa-miR The term "miR-150-3p" refers to the hsa-miR-150-3p gene set forth in SEQ ID NO: 6. miRBase Accession No. MIMAT0004610 and others Includes species homologs or orthologs. hsa-miR-150-3p gene Lagos-Quintana M et al., 2002, Curr Biol, vol. 12, The hsa-miR -150-3p is a precursor of hsa-mir-150, which has a hairpin-like structure. ” (miRBase Accession No. MI0000479, SEQ ID NO: 154 ) is known.

[0068] As used herein, "hsa-miR-6729-5p gene" or "hsa-mi The term "miR-6729-5p" refers to hsa-miR-6729-5p as set forth in SEQ ID NO: 7. p gene (miRBase Accession No. MIMAT0027359) It also includes homologs or orthologs from other species. The 5p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. 1 The "hsa-miR" can be obtained by the method described in JP-A-2004-1634-1645. -6729-5p is a precursor of hsa-mir-67, which has a hairpin-like structure. 29" (miRBase Accession No. MI0022574, SEQ ID NO: 1 55) is known.

[0069] As used herein, "hsa-miR-7641 gene" or "hsa-miR-7 The term "miR-7641" refers to the hsa-miR-7641 gene (miRB) set forth in SEQ ID NO: 8. ase Accession No. MIMAT0029782) and other species homologues The hsa-miR-7641 gene is a member of the Yoo J K et al., 2013, Arch Pharm Res, Vol. 36, p. 353-358 Furthermore, "hsa-miR-7641" can be obtained by the method described above. The hairpin-like structures of "hsa-mir-7641-1" and "hsa-mir-7 641-2” (miRBase Accession No. MI0024975, MI 0024976, SEQ ID NOs: 156, 157) are known.

[0070] As used herein, "hsa-miR-6765-3p gene" or "hsa-mi The term "hsa-miR-6765-3p" refers to hsa-miR-6765-3p as set forth in SEQ ID NO: 9. p gene (miRBase Accession No. MIMAT0027431) This includes homologs or orthologs from other species. The 3p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. 1 The "hsa-miR" can be obtained by the method described in JP-A-2004-1634-1645. -6765-3p is a precursor of hsa-mir-67, which has a hairpin-like structure. 65" (miRBase Accession No. MI0022610, SEQ ID NO: 1 58) is known.

[0071] As used herein, "hsa-miR-6820-5p gene" or "hsa-mi The term "miR-6820-5p" refers to hsa-miR-6820-5p as set forth in SEQ ID NO: 10. 5p gene (miRBase Accession No. MIMAT0027540) hsa-miR-6820 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6820-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 820" (miRBase Accession No. MI0022665, SEQ ID NO: 159) is known.

[0072] As used herein, "hsa-miR-575 gene" or "hsa-miR-57 The term "miR-575" refers to the hsa-miR-575 gene (miRBas) set forth in SEQ ID NO: 11. e Accession No. MIMAT0003240) and homologs in other species The hsa-miR-575 gene is a member of the Cummins JM et al., 2006, Proc Natl Acad Sci USA, vol. 103, p. 36 The "hsa-miR- The precursor of "hsa-mir-575" (mi 575) has a hairpin-like structure. RBase Accession No. MI0003582, sequence number 160) is known. It is being done.

[0073] As used herein, the term "hsa-miR-6836-3p gene" or "hsa-mi The term "miR-6836-3p" refers to hsa-miR-6836-3p as set forth in SEQ ID NO: 12. 3p gene (miRBase Accession No. MIMAT0027575) hsa-miR-6836 and other species homologs or orthologs. -3p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6836-3p is a precursor of hsa-mir-6, which has a hairpin-like structure. 836" (miRBase Accession No. MI0022682, SEQ ID NO: 161) is known.

[0074] As used herein, "hsa-miR-1469 gene" or "hsa-miR-1 The term "miR-1469" refers to the hsa-miR-1469 gene (miR Base Accession No. MIMAT0007347) and other species of Homo sapiens The hsa-miR-1469 gene is a member of the Kawa According to the method described in Ji H et al., 2008, BMC Genomics, Vol. 9, p. 157 hsa-miR-1469 can be obtained as a precursor of hsa-miR-1469. The miRBase Accession No. 1469 (hsa-mir-1469) has an apin-like structure. n No. MI0007074, SEQ ID NO: 162) is known.

[0075] As used herein, "hsa-miR-663a gene" or "hsa-miR-6 The term "miR-663a" refers to the hsa-miR-663a gene (miR Base Accession No. MIMAT0003326) and other species of Homo sapiens The hsa-miR-663a gene is a member of the Cummins family of miR-663a genes. ins JM et al., 2006, Proc Natl Acad Sci USA, vol. 103 It can be obtained by the method described in the "hsa- miR-663a has a hairpin-like structure as its precursor, hsa-mir-66 3a" (miRBase Accession No. MI0003672, SEQ ID NO: 1 63) is known.

[0076] As used herein, "hsa-miR-6075 gene" or "hsa-miR-6 The term "miR-6075" refers to the hsa-miR-6075 gene (miR-6075) set forth in SEQ ID NO: 15. Base Accession No. MIMAT0023700) and other species of Homo sapiens The hsa-miR-6075 gene is a gene encoding a miR-6075 gene. The method described in Lenkle C et al., 2012, RNA, Vol. 18, p. 472-484 Furthermore, "hsa-miR-6075" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-6075" (miRBase Accession No. on No. MI0020352, SEQ ID NO: 164) is known.

[0077] As used herein, "hsa-miR-4634 gene" or "hsa-miR-4 The term "miR-4634" refers to the hsa-miR-4634 gene (miR Base Accession No. MIMAT0019691) and other species of Homo sapiens The hsa-miR-4634 gene is a member of the Pers Son H et al., 2011, Cancer Res, Vol. 71, p. 78-86 hsa-miR-4634 can be obtained by the method described above. The miRBase Accession No. 100002666666 forms a hairpin-like structure. ion No. MI0017261, SEQ ID NO: 165) is known.

[0078] As used herein, "hsa-miR-423-5p gene" or "hsa-miR The term "miR-423-5p" refers to the hsa-miR-423-5p gene set forth in SEQ ID NO: 17. gene (miRBase Accession No. MIMAT0004748) and its This includes homologs or orthologs from other species. The gene is from Kasashima K et al., 2004, Biochem Biophys Re It can be obtained by the method described in s Commun, vol. 322, pp. 403-410. In addition, "hsa-miR-423-5p" has a hairpin-like structure as its precursor. Take "hsa-mir-423" (miRBase Accession No. MI0 001445, SEQ ID NO: 166) is known.

[0079] As used herein, "hsa-miR-4454 gene" or "hsa-miR-4 The term "miR-4454" refers to the hsa-miR-4454 gene (miR Base Accession No. MIMAT0018976) and other species of Homo sapiens The hsa-miR-4454 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4454 can be obtained as a precursor of The miRBase Accession No. 1001266666, which has an apin-like structure, is a member of the miRBase Accession No. 100126666666. n No. MI0016800, sequence number 167) is known.

[0080] As used herein, "hsa-miR-7109-5p gene" or "hsa-mi The term "hsa-miR-7109-5p" refers to hsa-miR-7109- 5p gene (miRBase Accession No. MIMAT0028115) hsa-miR-7109 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-7109-5p is a precursor of hsa-mir-7, which has a hairpin-like structure. 109" (miRBase Accession No. MI0022960, SEQ ID NO: 168) is known.

[0081] As used herein, "hsa-miR-6789-5p gene" or "hsa-mi The term "miR-6789-5p" refers to hsa-miR-6789-5p as set forth in SEQ ID NO: 20. 5p gene (miRBase Accession No. MIMAT0027478) hsa-miR-6789 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6789-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 789" (miRBase Accession No. MI0022634, SEQ ID NO: 169) is known.

[0082] As used herein, "hsa-miR-6877-5p gene" or "hsa-mi The term "miR-6877-5p" refers to hsa-miR-6877- 5p gene (miRBase Accession No. MIMAT0027654) hsa-miR-6877 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6877-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 877" (miRBase Accession No. MI0022724, SEQ ID NO: 170) is known.

[0083] As used herein, "hsa-miR-4792 gene" or "hsa-miR-4 The term "miR-4792" refers to the hsa-miR-4792 gene (miR-4792) set forth in SEQ ID NO: 22. Base Accession No. MIMAT0019964) and other species of Homo sapiens The hsa-miR-4792 gene is a member of the Pers Son H et al., 2011, Cancer Res, Vol. 71, p. 78-86 hsa-miR-4792 can be obtained by the method described above. The miRBase Accession No. 1002266666, which has a hairpin-like structure, is a missense mutation in the miR-1 gene. ion No. MI0017439, SEQ ID NO: 171) is known.

[0084] As used herein, "hsa-miR-4530 gene" or "hsa-miR-4 The term "miR-4530" refers to the hsa-miR-4530 gene (miR Base Accession No. MIMAT0019069) and other species of Homo sapiens The hsa-miR-4530 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 Furthermore, hsa-miR-4530 can be obtained as a precursor. The miRBase Accession No. 100001266666 (hsa-mir-4533) has an apin-like structure. n No. MI0016897, sequence number 172) is known.

[0085] As used herein, "hsa-miR-7975 gene" or "hsa-miR-7 The term "miR-7975" refers to the hsa-miR-7975 gene (miR Base Accession No. MIMAT0031178) and other species of Homo sapiens The hsa-miR-7975 gene is a member of the Velt family of miR-7975 genes. hut-Meikas A et al., 2013, Mol Endocrinol, online version Furthermore, "hsa-miR-7975" can be obtained by the method described in Its precursor, "hsa-mir-7975" (miRBase Accession No. MI0025751, SEQ ID NO: 173) is known.

[0086] As used herein, "hsa-miR-6724-5p gene" or "hsa-mi The term "miR-6724-5p" refers to hsa-miR-6724-5p as set forth in SEQ ID NO: 25. 5p gene (miRBase Accession No. MIMAT0025856) hsa-miR-6724 and other species homologs or orthologs. The -5p gene is described in Li Y et al., 2012, Gene, Vol. 497, p. 330-335. hsa-miR-6724-5p can be obtained by the method described in the literature. , and its precursor, "hsa-mir-6724" (miRBas e Accession No. MI0022559, SEQ ID NO: 174) is known .

[0087] As used herein, "hsa-miR-8073 gene" or "hsa-miR-8 The term "miR-8073" refers to the hsa-miR-8073 gene (miR-8073) set forth in SEQ ID NO: 26. Base Accession No. MIMAT0031000) and other species of Homo sapiens The hsa-miR-8073 gene includes genes encoding miR-8073, such as miR-1 and miR-2, and miR-3 and miR-4. HJ et al., 2013, Shock, Vol. 39, p. 480-487 Furthermore, "hsa-miR-8073" can be obtained by using hairpin as its precursor. The miRBase Accession No. 100001266664444422444 has a miR-like structure. No. MI0025909, SEQ ID NO: 175) is known.

[0088] As used herein, "hsa-miR-7977 gene" or "hsa-miR-7 The term "miR-7977" refers to the hsa-miR-7977 gene (miR Base Accession No. MIMAT0031180) and other species of Homo sapiens The hsa-miR-7977 gene is a member of the Velt hut-Meikas A et al., 2013, Mol Endocrinol, online version Furthermore, "hsa-miR-7977" can be obtained by the method described in Its precursor, "hsa-mir-7977" (miRBase Accession No. MI0025753, SEQ ID NO: 176) is known.

[0089] As used herein, "hsa-miR-1231 gene" or "hsa-miR-1 The term "miR-1231" refers to the hsa-miR-1231 gene (miR Base Accession No. MIMAT0005586) and other species of Homo sapiens The hsa-miR-1231 gene is a gene encoding a miR-1231 gene. Zikov E et al., 2007, Mol Cell, vol. 28, p328-336 Furthermore, "hsa-miR-1231" can be obtained by the method described above. The miRBase Accession No. 1231 (hsa-mir-1231) has a hairpin-like structure. The sequence number of the gene encoding the nucleotide sequence of the present invention is 177 (sequence number MI0006321).

[0090] As used herein, "hsa-miR-6799-5p gene" or "hsa-mi The term "miR-6799-5p" refers to hsa-miR-6799-5p as set forth in SEQ ID NO: 29. 5p gene (miRBase Accession No. MIMAT0027498) hsa-miR-6799 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6799-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 799" (miRBase Accession No. MI0022644, SEQ ID NO: 178) is known.

[0091] As used herein, "hsa-miR-615-5p gene" or "hsa-miR The term "miR-615-5p" refers to the hsa-miR-615-5p gene set forth in SEQ ID NO: 30. gene (miRBase Accession No. MIMAT0004804) and its This includes homologs or orthologs from other species. The gene is from Cummins JM et al., 2006, Proc Natl Acad Sci U It can be obtained by the method described in SA, Vol. 103, pp. 3687-3692. In addition, "hsa-miR-615-5p" has a hairpin-like structure as its precursor " hsa-mir-615” (miRBase Accession No. MI0003 628, SEQ ID NO: 179) is known.

[0092] As used herein, "hsa-miR-4450 gene" or "hsa-miR-4 The term "miR-4450" refers to the hsa-miR-4450 gene (miR Base Accession No. MIMAT0018971) and other species of Homo sapiens The hsa-miR-4450 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4450 can be obtained as a precursor of The miRBase Accession No. 100001266666 (hsa-mir-4450) has an apin-like structure. n No. MI0016795, SEQ ID NO: 180) is known.

[0093] As used herein, "hsa-miR-6726-5p gene" or "hsa-mi The term "miR-6726-5p" refers to hsa-miR-6726-5p as set forth in SEQ ID NO: 32. 5p gene (miRBase Accession No. MIMAT0027353) hsa-miR-6726 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6726-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 726" (miRBase Accession No. MI0022571, SEQ ID NO: 181) is known.

[0094] As used herein, "hsa-miR-6875-5p gene" or "hsa-mi The term "miR-6875-5p" refers to hsa-miR-6875- 5p gene (miRBase Accession No. MIMAT0027650) hsa-miR-6875 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6875-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 875" (miRBase Accession No. MI0022722, SEQ ID NO: 182) is known.

[0095] As used herein, "hsa-miR-4734 gene" or "hsa-miR-4 The term "miR-4734" refers to the hsa-miR-4734 gene (miR Base Accession No. MIMAT0019859) and other species of Homo sapiens The hsa-miR-4734 gene is a member of the Pers Son H et al., 2011, Cancer Res, Vol. 71, p. 78-86 hsa-miR-4734 can be obtained by the method described above. The miRBase Accession No. 100002666666 (hsa-mir-4734) forms a hairpin-like structure. ion No. MI0017371, SEQ ID NO: 183) is known.

[0096] As used herein, "hsa-miR-16-5p gene" or "hsa-miR- The term "miR-16-5p" refers to the hsa-miR-16-5p gene ( miRBase Accession No. MIMAT0000069) and other organisms The hsa-miR-16-5p gene includes species homologs or orthologs. Lagos-Quintana M et al., 2001, Science, Vol. 294, p. 85 3-858. -5p" has a hairpin-like structure as its precursor, "hsa-mir-16-1" and hsa-mir-16-2” (miRBase Accession No. MI000 0070, MI0000115, SEQ ID NOs: 184, 185) are known.

[0097] As used herein, "hsa-miR-602 gene" or "hsa-miR-60 The term "miR-602" refers to the hsa-miR-602 gene (miRBas) set forth in SEQ ID NO: 36. e Accession No. MIMAT0003270) and homologs in other species The hsa-miR-602 gene is a member of the Cummins JM et al., 2006, Proc Natl Acad Sci USA, vol. 103, p. 36 The "hsa-miR- 602” has a hairpin-like structure as its precursor “hsa-mir-602” (mi RBase Accession No. MI0003615, sequence number 186) It is being done.

[0098] As used herein, "hsa-miR-4651 gene" or "hsa-miR-4 The term "miR-4651" refers to the hsa-miR-4651 gene (miR Base Accession No. MIMAT0019715) and other species of Homo sapiens The hsa-miR-4651 gene is a member of the Pers Son H et al., 2011, Cancer Res, Vol. 71, p. 78-86 hsa-miR-4651 can be obtained by the method described above. The miRBase Accession No. 10010062663666 forms a hairpin-like structure. ion No. MI0017279, SEQ ID NO: 187) is known.

[0099] As used herein, "hsa-miR-8069 gene" or "hsa-miR-8 The term "miR-8069" refers to the hsa-miR-8069 gene (miR-8069) set forth in SEQ ID NO: 38. Base Accession No. MIMAT0030996) and other species of Homo sapiens The hsa-miR-8069 gene includes miR-logs, miR-1 and miR-2, and miR-3 and miR-4. HJ et al., 2013, Shock, Vol. 39, p. 480-487 In addition, "hsa-miR-8069" can be obtained by using hairpin as its precursor. The miRBase Accession No. 10000126 ... No. MI0025905, SEQ ID NO: 188) is known.

[0100] As used herein, "hsa-miR-1238-5p gene" or "hsa-mi The term "miR-1238-5p" refers to hsa-miR-1238-5p as set forth in SEQ ID NO: 39. 5p gene (miRBase Accession No. MIMAT0022947) hsa-miR-1238 and other species homologs or orthologs. The -5p gene is described in Berezikov E et al., 2007, Mol Cell, vol. 28, p. The "hsa-miR- 1238-5p is a precursor of hsa-mir-123, which has a hairpin-like structure. 8" (miRBase Accession No. MI0006328, SEQ ID NO: 18 9) is known.

[0101] As used herein, "hsa-miR-6880-5p gene" or "hsa-mi The term "miR-6880-5p" refers to hsa-miR-6880-5p as set forth in SEQ ID NO: 40. 5p gene (miRBase Accession No. MIMAT0027660) hsa-miR-6880 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6880-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 880" (miRBase Accession No. MI0022727, SEQ ID NO: 190) is known.

[0102] As used herein, "hsa-miR-8072 gene" or "hsa-miR-8 The term "miR-8072" refers to the hsa-miR-8072 gene (miR-8072) set forth in SEQ ID NO: 41. Base Accession No. MIMAT0030999) and other species of Homo sapiens The hsa-miR-8072 gene includes genes encoding miR-1 and miR-2, and ...2 and miR-3, and includes genes encoding miR-1 and miR-4, and includes genes encoding miR-2 and miR-5, and includes genes encoding miR-1 and miR-6, and includes genes encoding miR-1 and miR-4, and includes genes encoding miR-1 and miR-5, and includes genes encoding HJ et al., 2013, Shock, Vol. 39, p. 480-487 In addition, "hsa-miR-8072" can be obtained by using hairpin as its precursor. The miRBase Accession No. 1000012444444444 has a miR-like structure. No. MI0025908, SEQ ID NO: 191) is known.

[0103] As used herein, "hsa-miR-4723-5p gene" or "hsa-mi The term "miR-4723-5p" refers to hsa-miR-4723-5p as set forth in SEQ ID NO: 42. 5p gene (miRBase Accession No. MIMAT0019838) hsa-miR-4723 and other species homologs or orthologs. The -5p gene is described in Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. 23-5p" has a hairpin-like structure as its precursor, "hsa-mir-4723" (miRBase Accession No. MI0017359, SEQ ID NO: 192) is known.

[0104] As used herein, "hsa-miR-4732-5p gene" or "hsa-mi The term "miR-4732-5p" refers to hsa-miR-4732-5p as set forth in SEQ ID NO: 43. 5p gene (miRBase Accession No. MIMAT0019855) hsa-miR-4732 and other species homologs or orthologs. The -5p gene is described in Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. 32-5p" has a hairpin-like structure as its precursor, "hsa-mir-4732" (miRBase Accession No. MI0017369, SEQ ID NO: 193) is known.

[0105] As used herein, "hsa-miR-6125 gene" or "hsa-miR-6 The term "miR-6125" refers to the hsa-miR-6125 gene (miR-6125) set forth in SEQ ID NO: 44. Base Accession No. MIMAT0024598) and other species of Homo sapiens The hsa-miR-6125 gene is a member of the Smit h JL et al., 2012, J Virol, Vol. 86, p. 5278-5287 hsa-miR-6125 can be obtained by the method described above. The miRBase Accession No. 100002666666 (hsa-mir-6125) (miRBase Accession No. 1000026666666) forms a hairpin-like structure. ion No. MI0021259, SEQ ID NO: 194) is known.

[0106] As used herein, "hsa-miR-6090 gene" or "hsa-miR-6 The term "miR-6090" refers to the hsa-miR-6090 gene (miR-6090) set forth in SEQ ID NO: 45. Base Accession No. MIMAT0023715) and other species of Homo sapiens The hsa-miR-6090 gene is a member of the Yoo JK et al., 2012, Stem Cells Dev, Vol. 21, p. 2049-2057 hsa-miR-6090 can be obtained by the method described in the The precursor of "hsa-mir-6090" (miRBase A Accession No. MI0020367, SEQ ID NO: 195) is known.

[0107] As used herein, "hsa-miR-7114-5p gene" or "hsa-mi The term "miR-7114-5p" refers to hsa-miR-7114-5p as set forth in SEQ ID NO: 46. 5p gene (miRBase Accession No. MIMAT0028125) hsa-miR-7114 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-7114-5p is a precursor of hsa-mir-7, which has a hairpin-like structure. 114" (miRBase Accession No. MI0022965, SEQ ID NO: 196) is known.

[0108] As used herein, "hsa-miR-564 gene" or "hsa-miR-56 The term "miR-564" refers to the hsa-miR-564 gene (miRBas) set forth in SEQ ID NO: 47. e Accession No. MIMAT0003228) and homologs in other species The hsa-miR-564 gene is a member of the Cummins JM et al., 2006, Proc Natl Acad Sci USA, vol. 103, p. 36 The "hsa-miR- The precursor of "hsa-mir-564" (mi 564) has a hairpin-like structure. RBase Accession No. MI0003570, sequence number 197) It is being done.

[0109] As used herein, "hsa-miR-451a gene" or "hsa-miR-4 The term "miR-451a" refers to the hsa-miR-451a gene (miR Base Accession No. MIMAT0001631) and other species of Homo sapiens The hsa-miR-451a gene is a member of the Altu via Y et al., 2005, Nucleic Acids Res, Vol. 33, p2697- The miR-451 can be obtained by the method described in 2706. miR a has a hairpin-like structure as its precursor, hsa-mir-451a (miR Base Accession No. MI0001729, SEQ ID NO: 198) is known are.

[0110] As used herein, "hsa-miR-3135b gene" or "hsa-miR- The term "miR-3135b" refers to the hsa-miR-3135b gene ( miRBase Accession No. MIMAT0018985) and other organisms The hsa-miR-3135b gene includes species homologs or orthologs. Jima DD et al., 2010, Blood, vol. 116, e118-e127 hsa-miR-3135b can be obtained by the method described above. The miRBase Ac Accession No. MI0016809, SEQ ID NO: 199) is known.

[0111] As used herein, "hsa-miR-4497 gene" or "hsa-miR-4 The term "miR-4497" refers to the hsa-miR-4497 gene (miR Base Accession No. MIMAT0019032) and other species of Homo sapiens The hsa-miR-4497 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4497 can be obtained by The apin-like structure of "hsa-mir-4497" (miRBase Accession No. n No. MI0016859, sequence number 200) is known.

[0112] As used herein, "hsa-miR-4665-5p gene" or "hsa-mi The term "miR-4665-5p" refers to hsa-miR-4665-5p as set forth in SEQ ID NO: 51. 5p gene (miRBase Accession No. MIMAT0019739) hsa-miR-4665 and other species homologs or orthologs. The -5p gene is described in Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. "65-5p" has a hairpin-like structure as its precursor "hsa-mir-4665" (miRBase Accession No. MI0017295, SEQ ID NO: 201) is known.

[0113] As used herein, "hsa-miR-3622a-5p gene" or "hsa-m The term "miR-3622a-5p" refers to hsa-miR-3622a-5p as set forth in SEQ ID NO: 52. 2a-5p gene (miRBase Accession No. MIMAT00180 03) and other species homologs or orthologs. The 622a-5p gene is described in Witten D et al., 2010, BMC Biol, Vol. 8, p. 58. Also, "hsa-miR-3622a" can be obtained by the method described in -5p" has a hairpin-like structure as its precursor, "hsa-mir-3622a" ( miRBase Accession No. MI0016013, SEQ ID NO: 202) It is known.

[0114] As used herein, "hsa-miR-6850-5p gene" or "hsa-mi The term "miR-6850-5p" refers to hsa-miR-6850-5p as set forth in SEQ ID NO: 53. 5p gene (miRBase Accession No. MIMAT0027600) hsa-miR-6850 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6850-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 850" (miRBase Accession No. MI0022696, SEQ ID NO: 203) is known.

[0115] As used herein, "hsa-miR-6821-5p gene" or "hsa-mi The term "miR-6821-5p" refers to hsa-miR-6821-5p as set forth in SEQ ID NO: 54. 5p gene (miRBase Accession No. MIMAT0027542) hsa-miR-6821 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6821-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 821" (miRBase Accession No. MI0022666, SEQ ID NO: 204) is known.

[0116] As used herein, "hsa-miR-5100 gene" or "hsa-miR-5 The term "miR-5100" refers to the hsa-miR-5100 gene (miR-5100) set forth in SEQ ID NO: 55. Base Accession No. MIMAT0022259) and other species of Homo sapiens The hsa-miR-5100 gene is a member of the Tand The method described in M ​​et al., 2012, Oral Dis, Vol. 18, pp. 127-131 Furthermore, "hsa-miR-5100" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-5100" (miRBase Accession No. on No. MI0019116, SEQ ID NO: 205) is known.

[0117] As used herein, "hsa-miR-6872-3p gene" or "hsa-mi The term "miR-6872-3p" refers to hsa-miR-6872-3p as set forth in SEQ ID NO: 56. 3p gene (miRBase Accession No. MIMAT0027645) hsa-miR-6872 and other species homologs or orthologs. -3p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6872-3p is a precursor of hsa-mir-6, which has a hairpin-like structure. 872" (miRBase Accession No. MI0022719, SEQ ID NO: 206) is known.

[0118] As used herein, "hsa-miR-4433-3p gene" or "hsa-mi The term "miR-4433-3p" refers to hsa-miR-4433-3p as set forth in SEQ ID NO: 57. 3p gene (miRBase Accession No. MIMAT0018949) hsa-miR-4433 and other species homologs or orthologs. -3p gene is Jima DD et al., 2010, Blood, Vol. 116, e118-e The miR-4433 gene can be obtained by the method described in 127. -3p" has a hairpin-like structure as its precursor, "hsa-mir-4433" (m iRBase Accession No. MI0016773, sequence number 207) It is being done.

[0119] As used herein, "hsa-miR-1227-5p gene" or "hsa-mi The term "miR-1227-5p" refers to hsa-miR-1227-5p as set forth in SEQ ID NO: 58. 5p gene (miRBase Accession No. MIMAT0022941) hsa-miR-1227 and other species homologs or orthologs. The -5p gene is described in Berezikov E et al., 2007, Mol Cell, vol. 28, p. The "hsa-miR- 1227-5p is a precursor of hsa-mir-122, which has a hairpin-like structure. 7" (miRBase Accession No. MI0006316, SEQ ID NO: 20 8) is known.

[0120] As used herein, "hsa-miR-3188 gene" or "hsa-miR-3 The term "miR-3188" refers to the hsa-miR-3188 gene (miR-3188) set forth in SEQ ID NO: 59. Base Accession No. MIMAT0015070) and other species of Homo sapiens The hsa-miR-3188 gene is a member of the Star By the method described in k MS et al., 2010, PLoS One, Vol. 5, e9685 Furthermore, "hsa-miR-3188" can be obtained by using a hairpin "hsa-mir-3188" (miRBase Accession No. o.MI0014232, sequence number 209) is known.

[0121] As used herein, "hsa-miR-7704 gene" or "hsa-miR-7 The term "miR-7704" refers to the hsa-miR-7704 gene (miR Base Accession No. MIMAT0030019) and other species of Homo sapiens The hsa-miR-7704 gene is a member of the Swam inathan S et al., 2013, Biochem Biophys Res Commu It can be obtained by the method described in "N" Vol. 434, pp. 228-234. hsa-miR-7704 has a hairpin-like structure as its precursor, hsa-mi r-7704" (miRBase Accession No. MI0025240, Column number 210) is known.

[0122] As used herein, "hsa-miR-3185 gene" or "hsa-miR-3 The term "miR-3185" refers to the hsa-miR-3185 gene (miR-3185) set forth in SEQ ID NO: 61. Base Accession No. MIMAT0015065) and other species of Homo sapiens The hsa-miR-3185 gene is a member of the Star By the method described in k MS et al., 2010, PLoS One, Vol. 5, e9685 Furthermore, "hsa-miR-3185" can be obtained by using a hairpin "hsa-mir-3185" (miRBase Accession No. o.MI0014227, SEQ ID NO: 211) is known.

[0123] As used herein, "hsa-miR-1908-3p gene" or "hsa-mi The term "hsa-miR-1908-3p" refers to hsa-miR-1908- 3p gene (miRBase Accession No. MIMAT0026916) hsa-miR-1908 and other species homologs or orthologs. -3p gene is Bar M et al., 2008, Stem Cells, Vol. 26, p. 2496 The miR-19 can be obtained by the method described in JP-2505-2505. "08-3p" has a hairpin-like structure as its precursor "hsa-mir-1908" (miRBase Accession No. MI0008329, SEQ ID NO: 212) is known.

[0124] As used herein, "hsa-miR-6781-5p gene" or "hsa-mi The term "hsa-miR-6781-5p" refers to hsa-miR-6781- 5p gene (miRBase Accession No. MIMAT0027462) hsa-miR-6781 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6781-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 781" (miRBase Accession No. MI0022626, SEQ ID NO: 213) is known.

[0125] As used herein, "hsa-miR-6805-5p gene" or "hsa-mi The term "miR-6805-5p" refers to hsa-miR-6805-5p as set forth in SEQ ID NO: 64. 5p gene (miRBase Accession No. MIMAT0027510) hsa-miR-6805 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6805-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 805" (miRBase Accession No. MI0022650, SEQ ID NO: 214) is known.

[0126] As used herein, "hsa-miR-8089 gene" or "hsa-miR-8 The term "miR-8089" refers to the hsa-miR-8089 gene (miR-8089) set forth in SEQ ID NO: 65. Base Accession No. MIMAT0031016) and other species of Homo sapiens The hsa-miR-8089 gene includes miR-1 and miR-2, and includes miR-logs, miR-3 and miR-4, and miR-5 and miR-6, and miR-7 and miR-8, and miR-8 and miR-9 genes. HJ et al., 2013, Shock, Vol. 39, p. 480-487 Furthermore, "hsa-miR-8089" can be obtained by using hairpin as its precursor. The miRBase Accession No. 100001266664444 has a phosphodiesterase-like structure, "hsa-mir-8089" (miRBase Accession No. 100001266664444). No. MI0025925, SEQ ID NO: 215) is known.

[0127] As used herein, "hsa-miR-665 gene" or "hsa-miR-66 The term "miR-665" refers to the hsa-miR-665 gene (miRBas) set forth in SEQ ID NO: 66. e Accession No. MIMAT0004952) and homologs in other species The hsa-miR-665 gene is a member of the Bereziko V E et al., 2006, Genome Res, Vol. 16, p1289-1298 hsa-miR-665 can be obtained by the method described above. The miRBase Accession No. 100626665 (hsa-mir-665) forms a hairpin-like structure. ion No. MI0005563, SEQ ID NO: 216) is known.

[0128] As used herein, "hsa-miR-4486 gene" or "hsa-miR-4 The term "miR-4486" refers to the hsa-miR-4486 gene (miR Base Accession No. MIMAT0019020) and other species of Homo sapiens The hsa-miR-4486 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4486 can be obtained by The miRBase Accession No. hsa-mir-4486 (hsa-mir-4486) has an apin-like structure. n No. MI0016847, sequence number 217) is known.

[0129] As used herein, "hsa-miR-6722-3p gene" or "hsa-mi The term "miR-6722-3p" refers to hsa-miR-6722-3p as set forth in SEQ ID NO: 68. 3p gene (miRBase Accession No. MIMAT0025854) hsa-miR-6722 and other species homologs or orthologs. The -3p gene is described in Li Y et al., 2012, Gene, Vol. 497, p. 330-335. hsa-miR-6722-3p can be obtained by the method described in the literature. , and its precursor, "hsa-mir-6722" (miRBas e Accession No. MI0022557, SEQ ID NO: 218) is known .

[0130] As used herein, "hsa-miR-1260a gene" or "hsa-miR- The term "miR-1260a" refers to the hsa-miR-1260a gene ( miRBase Accession No. MIMAT0005911) and other organisms The hsa-miR-1260a gene includes species homologs or orthologs. Morin RD et al., 2008, Genome Res, vol. 18, pp. 610-621 hsa-miR-1260a can be obtained by the method described in the literature. The precursor of the miR gene, hsa-mir-1260a (miRBase Accession No. MI0006394, SEQ ID NO: 219) is known.

[0131] As used herein, "hsa-miR-4707-5p gene" or "hsa-mi The term "miR-4707-5p" refers to hsa-miR-4707-5p as set forth in SEQ ID NO: 70. 5p gene (miRBase Accession No. MIMAT0019807) hsa-miR-4707 and other species homologs or orthologs. The -5p gene is described in Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. "07-5p" has a hairpin-like structure as its precursor "hsa-mir-4707" (miRBase Accession No. MI0017340, SEQ ID NO: 220) is known.

[0132] As used herein, "hsa-miR-6741-5p gene" or "hsa-mi The term "miR-6741-5p" refers to hsa-miR-6741-5p as set forth in SEQ ID NO: 71. 5p gene (miRBase Accession No. MIMAT0027383) hsa-miR-6741 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6741-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 741" (miRBase Accession No. MI0022586, SEQ ID NO: 221) is known.

[0133] As used herein, "hsa-miR-1260b gene" or "hsa-miR- The term "miR-1260b" refers to the hsa-miR-1260b gene ( miRBase Accession No. MIMAT0015041) and other organisms The hsa-miR-1260b gene includes species homologs or orthologs. Method described in Stark MS et al., 2010, PLoS One, Vol. 5, e9685 Furthermore, "hsa-miR-1260b" can be obtained as its precursor. The miRBase Accession No. 1260b (hsa-mir-1260b) forms a hairpin-like structure. sion No. MI0014197, SEQ ID NO: 222) is known.

[0134] As used herein, "hsa-miR-1246 gene" or "hsa-miR-1 The term "miR-1246" refers to the hsa-miR-1246 gene (miR-1246) set forth in SEQ ID NO: 73. Base Accession No. MIMAT0005898) and other species of Homo sapiens The hsa-miR-1246 gene is a member of the Mori n RD et al., 2008, Genome Res, Vol. 18, p610-621 Furthermore, "hsa-miR-1246" can be obtained by the method described above. The miRBase Accession No. 100001246 (hsa-mir-1246) forms a hairpin-like structure. sion No. MI0006381, SEQ ID NO: 223) is known.

[0135] As used herein, "hsa-miR-6845-5p gene" or "hsa-mi The term "miR-6845-5p" refers to hsa-miR-6845-5p as set forth in SEQ ID NO: 74. 5p gene (miRBase Accession No. MIMAT0027590) hsa-miR-6845 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6845-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 845" (miRBase Accession No. MI0022691, SEQ ID NO: 224) is known.

[0136] As used herein, "hsa-miR-4638-5p gene" or "hsa-mi The term "miR-4638-5p" refers to hsa-miR-4638-5p as set forth in SEQ ID NO: 75. 5p gene (miRBase Accession No. MIMAT0019695) hsa-miR-4638 and other species homologs or orthologs. The -5p gene is described in Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. 38-5p" has a hairpin-like structure as its precursor, "hsa-mir-4638" (miRBase Accession No. MI0017265, SEQ ID NO: 225) is known.

[0137] As used herein, "hsa-miR-6085 gene" or "hsa-miR-6 The term "miR-6085" refers to the hsa-miR-6085 gene (miR-6085) set forth in SEQ ID NO: 76. Base Accession No. MIMAT0023710) and other species of Homo sapiens The hsa-miR-6085 gene is a gene encoding a miR-6085 gene. The method described in Lenkle C et al., 2012, RNA, Vol. 18, p. 472-484 Furthermore, "hsa-miR-6085" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-6085" (miRBase Accession No. on No. MI0020362, SEQ ID NO: 226) is known.

[0138] As used herein, "hsa-miR-1228-3p gene" or "hsa-mi The term "miR-1228-3p" refers to hsa-miR-1228-3p as set forth in SEQ ID NO: 77. 3p gene (miRBase Accession No. MIMAT0005583) hsa-miR-1228 and other species homologs or orthologs. The -3p gene is described in Berezikov E et al., 2007, Mol Cell, vol. 28, p. The "hsa-miR- 1228-3p is a precursor of hsa-mir-122, which has a hairpin-like structure. 8" (miRBase Accession No. MI0006318, SEQ ID NO: 22 7) is known.

[0139] As used herein, "hsa-miR-4534 gene" or "hsa-miR-4 The term "miR-4534" refers to the hsa-miR-4534 gene (miR Base Accession No. MIMAT0019073) and other species of Homo sapiens The hsa-miR-4534 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4534 can be obtained as a precursor of The miRBase Accession No. 100001266666 (hsa-mir-4534) has an apin-like structure. n No. MI0016901, sequence number 228) is known.

[0140] As used herein, "hsa-miR-5585-3p gene" or "hsa-mi The term "miR-5585-3p" refers to hsa-miR-5585-3p as set forth in SEQ ID NO: 79. 3p gene (miRBase Accession No. MIMAT0022286) hsa-miR-5585 and other species homologs or orthologs. The -3p gene is Friedlander MR et al., 2012, Nucleic Acids It can be obtained by the method described in ds Res, Vol. 40, pp. 37-52. "hsa-miR-5585-3p" has a hairpin-like structure as its precursor, "h sa-mir-5585” (miRBase Accession No.MI0019 142, SEQ ID NO: 229) is known.

[0141] As used herein, "hsa-miR-4741 gene" or "hsa-miR-4 The term "miR-4741" refers to the hsa-miR-4741 gene (miR-4741) set forth in SEQ ID NO: 80. Base Accession No. MIMAT0019871) and other species of Homo sapiens The hsa-miR-4741 gene is a member of the Pers Son H et al., 2011, Cancer Res, Vol. 71, p. 78-86 hsa-miR-4741 can be obtained by the method described above. The miRBase Accession No. 1001266666, which has a hairpin-like structure, is a missense mutation called "hsa-mir-4741" (miRBase Accession No. 100126666666). ion No. MI0017379, SEQ ID NO: 230) is known.

[0142] As used herein, "hsa-miR-4433b-3p gene" or "hsa-m The term "miR-4433b-3p" refers to hsa-miR-443 3b-3p gene (miRBase Accession No. MIMAT00304 14) and other species homologs or orthologs. The 433b-3p gene is Ple H et al., 2012, PLoS One, Vol. 7, e507 46. ​​Also, "hsa-miR-4433b" can be obtained by the method described in -3p" has a hairpin-like structure as its precursor "hsa-mir-4433b ( miRBase Accession No. MI0025511, SEQ ID NO: 231) It is known.

[0143] As used herein, "hsa-miR-197-5p gene" or "hsa-miR The term "miR-197-5p" refers to the hsa-miR-197-5p gene set forth in SEQ ID NO: 82. gene (miRBase Accession No. MIMAT0022691) and its This includes homologs or orthologs from other species. The gene is Lagos-Quintana M et al., 2003, RNA, vol. 9, p175- The miR-197- can be obtained by the method described in 179. 5p” has a hairpin-like structure as its precursor “hsa-mir-197” (miR Base Accession No. MI0000239, SEQ ID NO: 232) is known are.

[0144] As used herein, "hsa-miR-718 gene" or "hsa-miR-71 The term "miR-718" refers to the hsa-miR-718 gene (miRBas) set forth in SEQ ID NO: 83. e Accession No. MIMAT0012735) and homologs in other species The hsa-miR-718 gene is described by Artzi S et al. , 2008, BMC Bioinformatics, Vol. 9, p. 39 hsa-miR-718 can be obtained by The apin-like structure of "hsa-mir-718" (miRBase Accession No. No. MI0012489, SEQ ID NO: 233) is known.

[0145] As used herein, "hsa-miR-4513 gene" or "hsa-miR-4 The term "miR-4513" refers to the hsa-miR-4513 gene (miR Base Accession No. MIMAT0019050) and other species of Homo sapiens The hsa-miR-4513 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4513 can be obtained as a precursor of The miRBase Accession No. 1221126666 (hsa-mir-4513) has an apin-like structure. n No. MI0016879, sequence number 234) is known.

[0146] As used herein, "hsa-miR-4446-3p gene" or "hsa-mi The term "miR-4446-3p" refers to hsa-miR-4446-3p as set forth in SEQ ID NO: 85. 3p gene (miRBase Accession No. MIMAT0018965) hsa-miR-4446 and other species homologs or orthologs. -3p gene is Jima DD et al., 2010, Blood, Vol. 116, e118-e 127. Also, "hsa-miR-4446" can be obtained by the method described in -3p" has a hairpin-like structure as its precursor, "hsa-mir-4446" (m iRBase Accession No. MI0016789, sequence number 235) It is being done.

[0147] As used herein, "hsa-miR-619-5p gene" or "hsa-miR The term "miR-619-5p" refers to the hsa-miR-619-5p gene set forth in SEQ ID NO: 86. gene (miRBase Accession No. MIMAT0026622) and its This includes homologs or orthologs from other species. The gene is from Cummins JM et al., 2006, Proc Natl Acad Sci U It can be obtained by the method described in SA, Vol. 103, pp. 3687-3692. In addition, "hsa-miR-619-5p" has a hairpin-like structure as its precursor " hsa-mir-619” (miRBase Accession No. MI0003 633, SEQ ID NO: 236) is known.

[0148] As used herein, "hsa-miR-6816-5p gene" or "hsa-mi The term "miR-6816-5p" refers to hsa-miR-6816-5p as set forth in SEQ ID NO: 87. 5p gene (miRBase Accession No. MIMAT0027532) hsa-miR-6816 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6816-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 816" (miRBase Accession No. MI0022661, SEQ ID NO: 237) is known.

[0149] As used herein, "hsa-miR-6778-5p gene" or "hsa-mi The term "miR-6778-5p" refers to hsa-miR-6778-5p as set forth in SEQ ID NO: 88. 5p gene (miRBase Accession No. MIMAT0027456) hsa-miR-6778 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6778-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 778" (miRBase Accession No. MI0022623, SEQ ID NO: 238) is known.

[0150] As used herein, "hsa-miR-24-3p gene" or "hsa-miR- The term "miR-24-3p" refers to the hsa-miR-24-3p gene set forth in SEQ ID NO: 89 ( miRBase Accession No. MIMAT0000080) and other biological The hsa-miR-24-3p gene includes species homologs or orthologs. Lagos-Quintana M et al., 2001, Science, Vol. 294, p. 85 3-858. -3p has a hairpin-like structure as its precursor, "hsa-mir-24-1" and hsa-mir-24-2” (miRBase Accession No. MI000 0080, MI0000081, SEQ ID NOs: 239, 240) are known.

[0151] As used herein, "hsa-miR-1915-3p gene" or "hsa-mi The term "hsa-miR-1915-3p" refers to hsa-miR-1915- 3p gene (miRBase Accession No. MIMAT0007892) hsa-miR-1915 and other species homologs or orthologs. -3p gene is Bar M et al., 2008, Stem Cells, Vol. 26, p. 2496 The miR-19 can be obtained by the method described in JP-2505-2505. 15-3p has a hairpin-like structure as its precursor, hsa-mir-1915. (miRBase Accession No. MI0008336, SEQ ID NO: 241) is known.

[0152] As used herein, "hsa-miR-4665-3p gene" or "hsa-mi The term "miR-4665-3p" refers to hsa-miR-4665-3p as set forth in SEQ ID NO: 91. 3p gene (miRBase Accession No. MIMAT0019740) hsa-miR-4665 and other species homologs or orthologs. -3p gene is Persson H et al., 2011, Cancer Res, vol. 71, p. 78-86. "65-3p" has a hairpin-like structure as its precursor "hsa-mir-4665" (miRBase Accession No. MI0017295, SEQ ID NO: 201) is known.

[0153] As used herein, "hsa-miR-4449 gene" or "hsa-miR-4 The term "miR-4449" refers to the hsa-miR-4449 gene (miR Base Accession No. MIMAT0018968) and other species of Homo sapiens The hsa-miR-4449 gene is a member of the Jima The method described in DD et al., 2010, Blood, Vol. 116, e118-e127 hsa-miR-4449 can be obtained by The miRBase Accession No. 10 ... n No. MI0016792, sequence number 242) is known.

[0154] As used herein, "hsa-miR-6889-5p gene" or "hsa-mi The term "miR-6889-5p" refers to hsa-miR-6889-5p as set forth in SEQ ID NO: 93. 5p gene (miRBase Accession No. MIMAT0027678) hsa-miR-6889 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6889-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 889" (miRBase Accession No. MI0022736, SEQ ID NO: 243) is known.

[0155] As used herein, "hsa-miR-486-3p gene" or "hsa-miR The term "miR-486-3p" refers to the hsa-miR-486-3p gene set forth in SEQ ID NO: 94. gene (miRBase Accession No. MIMAT0004762) and its This includes homologs or orthologs from other species. The gene is Fu H et al., 2005, FEBS Lett, vol. 579, pp. 3849-3854 In addition, "hsa-miR-486-3p" can be obtained by the method described in The precursor of hsa-mir is a hairpin-like structure called hsa-mir-486 or hsa-mir- -486-2” (miRBase Accession No. MI0002470, M I0023622, SEQ ID NOs: 244, 245) are known.

[0156] As used herein, "hsa-miR-7113-3p gene" or "hsa-mi The term "hsa-miR-7113-3p" refers to hsa-miR-7113-3p as set forth in SEQ ID NO: 95. 3p gene (miRBase Accession No. MIMAT0028124) and other species homologs or orthologs. -3p gene is Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-7113-3p is a precursor of hsa-mir-7, which has a hairpin-like structure. 113" (miRBase Accession No. MI0022964, SEQ ID NO: 246) is known.

[0157] As used herein, "hsa-miR-642a-3p gene" or "hsa-mi The term "hsa-miR-642a-3p" refers to hsa-miR-642a-3p as set forth in SEQ ID NO: 96. 3p gene (miRBase Accession No. MIMAT0020924) and other species homologs or orthologs. The -3p gene is described in Cummins JM et al., 2006, Proc Natl Acad S ci USA, Vol. 103, pp. 3687-3692. In addition, "hsa-miR-642a-3p" has a hairpin-like structure as its precursor. The miRBase Accession No. MI0003657, SEQ ID NO: 247) is known.

[0158] As used herein, "hsa-miR-7847-3p gene" or "hsa-mi The term "miR-7847-3p" refers to hsa-miR-7847-3p as set forth in SEQ ID NO: 97. 3p gene (miRBase Accession No. MIMAT0030422) hsa-miR-7847 and other species homologs or orthologs. The -3p gene is described in Ple H et al., 2012, PLoS One, Vol. 7, e50746 hsa-miR-7847-3p can be obtained by the method described in the literature. , and its precursor, "hsa-mir-7847" (miRBas e Accession No. MI0025517, SEQ ID NO: 248) is known .

[0159] As used herein, "hsa-miR-6768-5p gene" or "hsa-mi The term "miR-6768-5p" refers to hsa-miR-6768-5p as set forth in SEQ ID NO: 98. 5p gene (miRBase Accession No. MIMAT0027436) hsa-miR-6768 and other species homologs or orthologs. The -5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, p. It can be obtained by the method described in 1634-1645. R-6768-5p is a precursor of hsa-mir-6, which has a hairpin-like structure. 768" (miRBase Accession No. MI0022613, SEQ ID NO: 249) is known.

[0160] As used herein, "hsa-miR-1290 gene" or "hsa-miR-1 The term "miR-1290" refers to the hsa-miR-1290 gene (miR Base Accession No. MIMAT0005880) and other species of Homo sapiens The hsa-miR-1290 gene is a member of the Mori n RD et al., 2008, Genome Res, Vol. 18, p610-621 hsa-miR-1290 can be obtained by the method described above. The miRBase Accession No. 10002266666, which has a hairpin-like structure, is a missense mutation of the miR-1290 gene. sion No. MI0006352, SEQ ID NO: 250) is known.

[0161] As used herein, "hsa-miR-7108-5p gene" or "hsa-mi The term "miR-7108-5p" refers to hsa-miR-7108 as set forth in SEQ ID NO: 100. -5p gene (miRBase Accession No. MIMAT0028113 ) and other species homologs or orthologs. The 8-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-7108-5p is a precursor of the hairpin-like structure known as hsa-mir- 7108" (miRBase Accession No. MI0022959, sequence no. No. 251) is known.

[0162] As used herein, "hsa-miR-92b-5p gene" or "hsa-miR The term "miR-92b-5p" refers to hsa-miR-92b-5p as set forth in SEQ ID NO: 101. Gene (miRBase Accession No. MIMAT0004792) and This includes homologs or orthologs of hsa-miR-92b-5p from other species. Genes are listed in Cummins JM et al., 2006, Proc Natl Acad Sci USA, Vol. 103, pp. 3687-3692. In addition, "hsa-miR-92b-5p" has a hairpin-like structure as its precursor. "hsa-mir-92b" (miRBase Accession No. MI000 3560, SEQ ID NO: 252) is known.

[0163] As used herein, "hsa-miR-663b gene" or "hsa-miR-6 The term "miR-663b" refers to the hsa-miR-663b gene (mi RBase Accession No. MIMAT0005867) and other species The hsa-miR-663b gene is a homologue or ortholog. ada S et al., 2008, Leukemia, Vol. 22, p. 1274-1278 hsa-miR-663b can be obtained by the method described above. The miRBase Accelerator has a hairpin-like structure called "hsa-mir-663b" ( Session No. MI0006336, SEQ ID NO: 253) is known.

[0164] As used herein, "hsa-miR-3940-5p gene" or "hsa-mi The term "miR-3940-5p" refers to hsa-miR-3940 as set forth in SEQ ID NO: 103. -5p gene (miRBase Accession No. MIMAT0019229 ) and other species homologs or orthologs. The 0-5p gene is Liao JY et al., 2010, PLoS One, Vol. 5, e1056 The miR-3940-5 gene can be obtained by the method described in 3. p” has a hairpin-like structure as its precursor “hsa-mir-3940” (miR Base Accession No. MI0016597, SEQ ID NO: 254) is known are.

[0165] As used herein, "hsa-miR-4467 gene" or "hsa-miR-4 The term "miR-4467" refers to the hsa-miR-4467 gene (miR-4467) set forth in SEQ ID NO: 104. RBase Accession No. MIMAT0018994) and other species The hsa-miR-4467 gene is a homologue or ortholog of the Jim a Method described in DD et al., 2010, Blood, Vol. 116, p. e118-e127 Furthermore, "hsa-miR-4467" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-4467" (miRBase Accession No. on No. MI0016818, SEQ ID NO: 255) is known.

[0166] As used herein, "hsa-miR-6858-5p gene" or "hsa-mi The term "miR-6858-5p" refers to hsa-miR-6858 as set forth in SEQ ID NO: 105. -5p gene (miRBase Accession No. MIMAT0027616 ) and other species homologs or orthologs. The 8-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6858-5p is a precursor of the hairpin-like structure known as hsa-mir- 6858" (miRBase Accession No. MI0022704, sequence no. No. 256) is known.

[0167] As used herein, "hsa-miR-4417 gene" or "hsa-miR-4 The term "miR-4417" refers to the hsa-miR-4417 gene (miR-4417) set forth in SEQ ID NO: 106. RBase Accession No. MIMAT0018929) and other species The hsa-miR-4417 gene is a homologue or ortholog of the Jim a Method described in DD et al., 2010, Blood, Vol. 116, p. e118-e127 In addition, "hsa-miR-4417" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-4417" (miRBase Accession No. on No. MI0016753, SEQ ID NO: 257) is known.

[0168] As used herein, "hsa-miR-3665 gene" or "hsa-miR-3 The term "miR-3665" refers to the hsa-miR-3665 gene (miR-3665) set forth in SEQ ID NO: 107. RBase Accession No. MIMAT0018087) and other species The hsa-miR-3665 gene is a homologue or ortholog of the Xie According to the method described in X et al., 2005, Nature, Vol. 434, pp. 338-345 In addition, "hsa-miR-3665" can be obtained by The pin-like structure of "hsa-mir-3665" (miRBase Accession No. No. MI0016066, SEQ ID NO: 258) is known.

[0169] As used herein, "hsa-miR-4736 gene" or "hsa-miR-4 The term "miR-4736" refers to the hsa-miR-4736 gene (miR-4736) set forth in SEQ ID NO: 108. RBase Accession No. MIMAT0019862) and other species The hsa-miR-4736 gene is a homologue or ortholog. Published in sson H et al., 2011, Cancer Res, Vol. 71, p78-86 hsa-miR-4736 can be obtained by the method described above. The miRBase Accession No. 100001264489444444444444 is a miR-based gene that forms a hairpin-like structure. sion No. MI0017373, SEQ ID NO: 259) is known.

[0170] As used herein, "hsa-miR-4687-3p gene" or "hsa-mi The term "miR-4687-3p" refers to hsa-miR-4687 set forth in SEQ ID NO: 109. -3p gene (miRBase Accession No. MIMAT0019775 ) and other species homologs or orthologs. The 7-3p gene is described in Persson H et al., 2011, Cancer Res, Vol. 71, The miR-4 gene can be obtained by the method described on pages 78-86 of this specification. 687-3p has a hairpin-like structure as its precursor, hsa-mir-4687 ” (miRBase Accession No. MI0017319, SEQ ID NO: 260 ) is known.

[0171] As used herein, "hsa-miR-1908-5p gene" or "hsa-mi The term "miR-1908-5p" refers to hsa-miR-1908 as set forth in SEQ ID NO: 110. -5p gene (miRBase Accession No. MIMAT0007881 ) and other species homologs or orthologs. The 8-5p gene is described in Bar M et al., 2008, Stem Cells, Vol. 26, p. 249. The miR-1 gene can be obtained by the method described in JP-A-2006-2505. 908-5p is a precursor of hsa-mir-1908, which has a hairpin-like structure. ” (miRBase Accession No. MI0008329, SEQ ID NO: 212 ) is known.

[0172] As used herein, "hsa-miR-5195-3p gene" or "hsa-mi The term "miR-5195-3p" refers to hsa-miR-5195 as set forth in SEQ ID NO: 111. -3p gene (miRBase Accession No. MIMAT0021127 ) and other species homologs or orthologs. The 5-3p gene is described in Schotte D et al., 2011, Leukemia, Vol. 25, p. It can be obtained by the method described in 1389-1399. R-5195-3p is a precursor of hsa-mir-5, which has a hairpin-like structure. 195" (miRBase Accession No. MI0018174, SEQ ID NO: 261) is known.

[0173] As used herein, "hsa-miR-4286 gene" or "hsa-miR-4 The term "miR-4286" refers to the hsa-miR-4286 gene (miR-4286) set forth in SEQ ID NO: 112. RBase Accession No. MIMAT0016916) and other species The hsa-miR-4286 gene is a homologue or ortholog of the Gof f By the method described in LA et al., 2009, PLoS One, Vol. 4, e7192 Furthermore, "hsa-miR-4286" can be obtained by using a hairpin The miRBase Accession No. 100001266444444 has a similar structure to "hsa-mir-4286" (miRBase Accession No. 1000012664 ...). o.MI0015894, SEQ ID NO: 262) is known.

[0174] As used herein, "hsa-miR-3679-3p gene" or "hsa-mi The term "miR-3679-3p" refers to hsa-miR-3679 as set forth in SEQ ID NO: 113. -3p gene (miRBase Accession No. MIMAT0018105 ) and other species homologs or orthologs. The 9-3p gene is described in Creighton CJ et al., 2010, PLoS One, Vol. 5, The miR-36 gene can be obtained by the method described in e9637. "79-3p" has a hairpin-like structure as its precursor "hsa-mir-3679" (miRBase Accession No. MI0016080, SEQ ID NO: 263) is known.

[0175] As used herein, "hsa-miR-6791-5p gene" or "hsa-mi The term "miR-6791-5p" refers to hsa-miR-6791 set forth in SEQ ID NO: 114. -5p gene (miRBase Accession No. MIMAT0027482 ) and other species homologs or orthologs. The 1-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6791-5p is a precursor of the hairpin-like structure known as hsa-mir- 6791" (miRBase Accession No. MI0022636, sequence no. No. 264) is known.

[0176] As used herein, "hsa-miR-1202 gene" or "hsa-miR-1 The term "miR-1202" refers to the hsa-miR-1202 gene (miR-1202) set forth in SEQ ID NO: 115. RBase Accession No. MIMAT0005865) and other species The hsa-miR-1202 gene is a homologue or ortholog. ton S et al., 2008, Leukemia, Vol. 22, p. 330-338 hsa-miR-1202 can be obtained by the method described above. The miRBase Accession No. 1202 (hsa-mir-1202) forms a hairpin-like structure. sion No. MI0006334, SEQ ID NO: 265) is known.

[0177] As used herein, "hsa-miR-3656 gene" or "hsa-miR-3 The term "miR-3656" refers to the hsa-miR-3656 gene (miR-3656) set forth in SEQ ID NO: 116. RBase Accession No. MIMAT0018076) and other species The hsa-miR-3656 gene includes homologs or orthologs. ri E et al., 2010, Nucleic Acids Res, Vol. 38, p6234-6 246. " has a hairpin-like structure as its precursor "hsa-mir-3656" (miRB The enzyme (Accession No. MI0016056, SEQ ID NO: 266) is known There are.

[0178] As used herein, "hsa-miR-4746-3p gene" or "hsa-mi The term "miR-4746-3p" refers to hsa-miR-4746 as set forth in SEQ ID NO: 117. -3p gene (miRBase Accession No. MIMAT0019881 ) and other species homologs or orthologs. The 6-3p gene is described in Persson H et al., 2011, Cancer Res, Vol. 71, The miR-4 gene can be obtained by the method described on pages 78-86 of this specification. 746-3p is a precursor of hsa-mir-4746, which has a hairpin-like structure. ” (miRBase Accession No. MI0017385, SEQ ID NO: 267 ) is known.

[0179] As used herein, "hsa-miR-3184-5p gene" or "hsa-mi The term "miR-3184-5p" refers to hsa-miR-3184 set forth in SEQ ID NO: 118. -5p gene (miRBase Accession No. MIMAT0015064 ) and other species homologs or orthologs. The 4-5p genes are described in Stark MS et al., 2010, PLoS One, Vol. 5, e968 5. Also, "hsa-miR-3184-5 p” has a hairpin-like structure as its precursor “hsa-mir-3184” (miR Base Accession No. MI0014226, SEQ ID NO: 268) is known are.

[0180] As used herein, "hsa-miR-3937 gene" or "hsa-miR-3 The term "miR-3937" refers to the hsa-miR-3937 gene (miR-3937) set forth in SEQ ID NO: 119. RBase Accession No. MIMAT0018352) and other species The hsa-miR-3937 gene is a homologue or ortholog of the Lia o JY et al., 2010, PLoS One, Vol. 5, e10563 In addition, "hsa-miR-3937" can be obtained by using hairpin as its precursor. The miRBase Accession No. 100001266344444 has a phosphodiesterase-like structure, "hsa-mir-3937" (miRBase Accession No. 1000012663444444). No. MI0016593, SEQ ID NO: 269) is known.

[0181] As used herein, "hsa-miR-6515-3p gene" or "hsa-mi The term "miR-6515-3p" refers to hsa-miR-6515 as set forth in SEQ ID NO: 120. -3p gene (miRBase Accession No. MIMAT0025487 ) and other species homologs or orthologs. The 5-3p gene is Joyce CE et al., 2011, Hum Mol Genet, 20 It can be obtained by the method described in Vol. 1, pp. 4025-4040. -miR-6515-3p has a hairpin-like structure as its precursor, "hsa-mi r-6515” (miRBase Accession No. MI0022227, Column number 270) is known.

[0182] As used herein, "hsa-miR-6132 gene" or "hsa-miR-6 The term "miR-6132" refers to the hsa-miR-6132 gene (miR-6132) set forth in SEQ ID NO: 121. RBase Accession No. MIMAT0024616) and other species The hsa-miR-6132 gene is a homologue or ortholog. Nemann M et al., 2012, Genome Biol Evol, vol. 4, p552- 564. Also, "hsa-miR-6132" can be obtained by the method described in " has a hairpin-like structure as its precursor, "hsa-mir-6132" (miRB The enzyme (Accession No. MI0021277, SEQ ID NO: 271) is known There are.

[0183] As used herein, "hsa-miR-187-5p gene" or "hsa-miR The term "miR-187-5p" refers to hsa-miR-187-5p as set forth in SEQ ID NO: 122. Gene (miRBase Accession No. MIMAT0004561) and It includes homologs or orthologs of other species. The gene is described in Lim LP et al., 2003, Science, Vol. 299, p. 1540. Furthermore, "hsa-miR-187-5p" can be obtained by the method described above. The precursor of the hairpin-like structure "hsa-mir-187" (miRBase A Accession No. MI0000274, SEQ ID NO: 272) is known.

[0184] As used herein, "hsa-miR-7111-5p gene" or "hsa-mi The term "miR-7111-5p" refers to hsa-miR-7111 set forth in SEQ ID NO: 123. -5p gene (miRBase Accession No. MIMAT0028119 ) and other species homologs or orthologs. The 1-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-7111-5p is a precursor of the hairpin-like structure known as hsa-mir- 7111" (miRBase Accession No. MI0022962, sequence no. No. 273) is known.

[0185] As used herein, "hsa-miR-5787 gene" or "hsa-miR-5 The term "miR-5787" refers to the hsa-miR-5787 gene (miR-5787) set forth in SEQ ID NO: 124. RBase Accession No. MIMAT0023252) and other species The hsa-miR-5787 gene is a homologue or ortholog of the Yoo H et al., 2011, Biochem Biophys Res Commun, vol. 415, The miR gene can be obtained by the method described on pages 567-572. -5787" has a hairpin-like structure as its precursor, "hsa-mir-5787" (miRBase Accession No. MI0019797, SEQ ID NO: 274) is known.

[0186] As used herein, "hsa-miR-6779-5p gene" or "hsa-mi The term "miR-6779-5p" refers to hsa-miR-6779 set forth in SEQ ID NO: 125. -5p gene (miRBase Accession No. MIMAT0027458 ) and other species homologs or orthologs. The 9-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6779-5p is a precursor of the hairpin-like structure known as hsa-mir- 6779" (miRBase Accession No. MI0022624, sequence no. No. 275) is known.

[0187] As used herein, "hsa-miR-6808-5p gene" or "hsa-mi The term "miR-6808-5p" refers to hsa-miR-6808 as set forth in SEQ ID NO: 126. -5p gene (miRBase Accession No. MIMAT0027516 ) and other species homologs or orthologs. The 8-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6808-5p is a precursor of the hairpin-like structure known as hsa-mir- 6808" (miRBase Accession No. MI0022653, sequence no. No. 276) is known.

[0188] As used herein, "hsa-miR-6774-5p gene" or "hsa-mi The term "miR-6774-5p" refers to hsa-miR-6774 set forth in SEQ ID NO: 127. -5p gene (miRBase Accession No. MIMAT0027448 ) and other species homologs or orthologs. The 4-5p genes are described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6774-5p is a precursor of the hairpin-like structure known as hsa-mir- 6774" (miRBase Accession No. MI0022619, sequence no. No. 277) is known.

[0189] As used herein, "hsa-miR-4656 gene" or "hsa-miR-4 The term "miR-4656" refers to the hsa-miR-4656 gene (miR-4656) set forth in SEQ ID NO: 128. RBase Accession No. MIMAT0019723) and other species The hsa-miR-4656 gene is a homologue or ortholog. Published in sson H et al., 2011, Cancer Res, Vol. 71, p78-86 hsa-miR-4656 can be obtained by the method described above. The miRBase Accession No. 100001266686626444444444 sion No. MI0017284, SEQ ID NO: 278) is known.

[0190] As used herein, "hsa-miR-6806-5p gene" or "hsa-mi The term "miR-6806-5p" refers to hsa-miR-6806 set forth in SEQ ID NO: 129. -5p gene (miRBase Accession No. MIMAT0027512 ) and other species homologs or orthologs. The 6-5p gene is described in Ladewig E et al., 2012, Genome Res, vol. 22, It can be obtained by the method described on pages 1634-1645. iR-6806-5p is a precursor of the hairpin-like structure known as hsa-mir- 6806" (miRBase Accession No. MI0022651, sequence no. No. 279) is known.

[0191] As used herein, "hsa-miR-1233-5p gene" or "hsa-mi The term "miR-1233-5p" refers to hsa-miR-1233 as set forth in SEQ ID NO: 130. -5p gene (miRBase Accession No. MIMAT0022943 ) and other species homologs or orthologs. The 3-5p gene is described in Berezikov E et al., 2007, Mol Cell, vol. 28, The miR gene can be obtained by the method described on pages 328-336. -1233-5p is a precursor of hsa-mir-12, which has a hairpin-like structure. 33-1”, “hsa-mir-1233-2” (miRBase Accession No. MI0006323, MI0015973, SEQ ID NO: 280, 281) are known are.

[0192] As used herein, "hsa-miR-328-5p gene" or "hsa-miR The term "miR-328-5p" refers to hsa-miR-328-5p as set forth in SEQ ID NO: 131. Gene (miRBase Accession No. MIMAT0026486) and This includes homologs or orthologs of other species. The gene is from Kim J et al., 2004, Proc Natl Acad Sci USA, It can be obtained by the method described in Vol. 101, pp. 360-365. a-miR-328-5p has a hairpin-like structure as its precursor, hsa-mi r-328" (miRBase Accession No. MI0000804, sequence Number 282) is known.

[0193] As used herein, "hsa-miR-4674 gene" or "hsa-miR-4 The term "miR-4674" refers to the hsa-miR-4674 gene (miR-4674) set forth in SEQ ID NO: 132. RBase Accession No. MIMAT0019756) and other species The hsa-miR-4674 gene is a homologue or ortholog of the Per Published in sson H et al., 2011, Cancer Res, Vol. 71, p78-86 hsa-miR-4674 can be obtained by the method described above. The miRBase Accession No. 1000012666666 forms a hairpin-like structure. sion No. MI0017305, SEQ ID NO: 283) is known.

[0194] As used herein, "hsa-miR-2110 gene" or "hsa-miR-2 The term "miR-2110" refers to the hsa-miR-2110 gene (miR-2110) set forth in SEQ ID NO: 133. RBase Accession No. MIMAT0010133) and other species The hsa-miR-2110 gene includes homologs or orthologs. The method described in JY et al., 2009, J Virol, Vol. 83, pp. 3333-3341 Furthermore, "hsa-miR-2110" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-2110" (miRBase Accession No. on No. MI0010629, SEQ ID NO: 284) is known.

[0195] As used herein, "hsa-miR-6076 gene" or "hsa-miR-6 The term "miR-6076" refers to the hsa-miR-6076 gene (miR-6076) set forth in SEQ ID NO: 134. RBase Accession No. MIMAT0023701) and other species The hsa-miR-6076 gene is a homologue or ortholog of the Voe The method described in Illenkle C et al., 2012, RNA, Vol. 18, p. 472-484 hsa-miR-6076 can be obtained by the method described above. The miRBase Accession No. 10000266 (hsa-mir-6076) has a hairpin-like structure. ion No. MI0020353, SEQ ID NO: 285) is known.

[0196] As used herein, "hsa-miR-3619-3p gene" or "hsa-mi The term "miR-3619-3p" refers to hsa-miR-3619 as set forth in SEQ ID NO: 135. -3p gene (miRBase Accession No. MIMAT0019219 ) and other species homologs or orthologs. The 9-3p gene is described in Witten D et al., 2010, BMC Biol, Vol. 8, p. 58. The "hsa-miR-3619-3p" can be obtained by the method described in the literature. The precursor of miRBa is “hsa-mir-3619” (miRBa (Accession No. MI0016009, SEQ ID NO: 286) do.

[0197] As used herein, "hsa-miR-92a-2-5p gene" or "hsa-m The term "miR-92a-2-5p" refers to hsa-miR-92a-2-5p as set forth in SEQ ID NO: 136. a-2-5p gene (miRBase Accession No. MIMAT0004 508) and other species homologs or orthologs. The 92a-2-5p gene was identified in Mourelatos Z et al., 2002, Genes De It can be obtained by the method described in Vol. 16, pp. 720-728. sa-miR-92a-2-5p is a precursor of the hairpin-like structure known as hsa -mir-92a-2” (miRBase Accession No. MI00000 94, SEQ ID NO: 287) is known.

[0198] As used herein, "hsa-miR-128-1-5p gene" or "hsa-m The term "miR-128-1-5p" refers to hsa-miR-128-1-5p as set forth in SEQ ID NO: 137. 8-1-5p gene (miRBase Accession No. MIMAT0026 477) and other species homologs or orthologs. The 128-1-5p gene is Lagos-Quintana M et al., 2002, Cur It can be obtained by the method described in rBiol, vol. 12, pp. 735-739. In addition, "hsa-miR-128-1-5p" has a hairpin-like structure as its precursor. "hsa-mir-128-1" (miRBase Accession No. MI 0000447, SEQ ID NO: 288) is known.

[0199] As used herein, "hsa-miR-638 gene" or "hsa-miR-63 The term "miR-638" refers to the hsa-miR-638 gene (miRBa se Accession No. MIMAT0003308) and other species homologs The hsa-miR-638 gene is also included in the Cummins JM et al., 2006, Proc Natl Acad Sci USA, vol. 103, p. 3 The "hsa-miR" can be obtained by the method described in US Pat. The precursor of mir-638 is a hairpin-like structure called hsa-mir-638 (m iRBase Accession No. MI0003653, sequence number 289) It is being done.

[0200] As used herein, "hsa-miR-2861 gene" or "hsa-miR-2 The term "miR-2861" refers to the hsa-miR-2861 gene (miR-2861) set forth in SEQ ID NO: 139. RBase Accession No. MIMAT0013802) and other species The hsa-miR-2861 gene is a homologue or ortholog. H et al., 2009, J Clin Invest, Vol. 119, p3666-3677 hsa-miR-2861 can be obtained by the method described above. The miRBase Ac receptor has a hairpin-like structure as a precursor. Accession No. MI0013006, SEQ ID NO: 290) is known.

[0201] As used herein, "hsa-miR-371a-5p gene" or "hsa-mi The term "miR-371a-5p" refers to hsa-miR-371a as set forth in SEQ ID NO: 140. -5p gene (miRBase Accession No. MIMAT0004687 ) and other species homologs or orthologs. The a-5p gene is described in Suh MR et al., 2004, Dev Biol, vol. 270, p. 488. The miR-371 can be obtained by the method described in Ref. 498. a-5p" is a precursor of "hsa-mir-371a" ( miRBase Accession No. MI0000779, SEQ ID NO: 291) It is known.

[0202] As used herein, "hsa-miR-211-3p gene" or "hsa-miR The term "miR-211-3p" refers to hsa-miR-211-3p set forth in SEQ ID NO: 141. Gene (miRBase Accession No. MIMAT0022694) and It includes homologs or orthologs of other species. The gene is described in Lim LP et al., 2003, Science, Vol. 299, p. 1540. Furthermore, "hsa-miR-211-3p" can be obtained by the method described above. The precursor of the hairpin-like structure "hsa-mir-211" (miRBase A Accession No. MI0000287, SEQ ID NO: 292) is known.

[0203] As used herein, "hsa-miR-1273g-3p gene" or "hsa-m The term "hsa-miR-1273g-3p" refers to hsa-miR-12 73g-3p gene (miRBase Accession No. MIMAT0022 742) and other species homologs or orthologs. The 1273g-3p gene is described in Reshmi G et al., 2011, Genomics, 97 It can be obtained by the method described in Vol. 1, pp. 333-340. iR-1273g-3p is a precursor of hsa-mir, which has a hairpin-like structure. -1273g” (miRBase Accession No. MI0018003, Column number 293) is known.

[0204] As used herein, "hsa-miR-1203 gene" or "hsa-miR-1 The term "miR-1203" refers to the hsa-miR-1203 gene (miR-1203) set forth in SEQ ID NO: 143. RBase Accession No. MIMAT0005866) and other species The hsa-miR-1203 gene is a homologue or ortholog. ton S et al., 2008, Leukemia, Vol. 22, p. 330-338 Furthermore, "hsa-miR-1203" can be obtained by the method described above. The miRBase Accession No. 1000026666444444 forms a hairpin-like structure. sion No. MI0006335, SEQ ID NO: 294) is known.

[0205] As used herein, "hsa-miR-122-5p gene" or "hsa-miR The term "miR-122-5p" refers to hsa-miR-122-5p as set forth in SEQ ID NO: 144. Gene (miRBase Accession No. MIMAT0000421) and It includes homologs or orthologs of other species. Genes are listed in Lagos-Quintana M et al., 2002, Curr Biol, 12 It can be obtained by the method described in Vol. 1, pp. 735-739. iR-122-5p is a precursor of hsa-mir-1, which has a hairpin-like structure. 22" (miRBase Accession No. MI0000442, SEQ ID NO: 2 95) is known.

[0206] As used herein, "hsa-miR-4258 gene" or "hsa-miR-4 The term "miR-4258" refers to the hsa-miR-4258 gene (miR-4258) set forth in SEQ ID NO: 145. RBase Accession No. MIMAT0016879) and other species The hsa-miR-4258 gene is a homologue or ortholog of Gof f By the method described in LA et al., 2009, PLoS One, Vol. 4, e7192 Furthermore, "hsa-miR-4258" can be obtained by using a hairpin "hsa-mir-4258" (miRBase Accession No. o.MI0015857, sequence number 296) is known.

[0207] As used herein, "hsa-miR-4484 gene" or "hsa-miR-4 The term "miR-4484" refers to the hsa-miR-4484 gene (miR-4484) set forth in SEQ ID NO: 146. RBase Accession No. MIMAT0019018) and other species The hsa-miR-4484 gene is a homologue or ortholog of the Jim a Method described in DD et al., 2010, Blood, Vol. 116, p. e118-e127 Furthermore, "hsa-miR-4484" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-4484" (miRBase Accession No. on No. MI0016845, SEQ ID NO: 297) is known.

[0208] As used herein, "hsa-miR-4648 gene" or "hsa-miR-4 The term "miR-4648" refers to the hsa-miR-4648 gene (miR-4648) set forth in SEQ ID NO: 147. RBase Accession No. MIMAT0019710) and other species The hsa-miR-4648 gene is a homologue or ortholog. Published in sson H et al., 2011, Cancer Res, Vol. 71, p78-86 hsa-miR-4648 can be obtained by the method described above. The miRBase Accession No. 10000126666688 (hsa-mir-4648) forms a hairpin-like structure. sion No. MI0017275, SEQ ID NO: 298) is known.

[0209] As used herein, "hsa-miR-6780b-5p gene" or "hsa-m The term "miR-6780b-5p" refers to hsa-miR-6780b-5p as set forth in SEQ ID NO: 148. 80b-5p gene (miRBase Accession No. MIMAT0027 572) and other species homologs or orthologs. The 6780b-5p gene is from Ladewig E et al., 2012, Genome Res. It can be obtained by the method described in Vol. 22, pp. 1634-1645. sa-miR-6780b-5p has a hairpin-like structure as its precursor, hsa -mir-6780b” (miRBase Accession No. MI00226 81, SEQ ID NO: 299) is known.

[0210] As used herein, "hsa-miR-4516 gene" or "hsa-miR-4 The term "miR-4516" refers to the hsa-miR-4516 gene (miR-4516) set forth in SEQ ID NO: 466. RBase Accession No. MIMAT0019053) and other species The hsa-miR-4516 gene is a homologue or ortholog. Ma DD et al., 2010, Blood. Vol. 116, e118-e127 Furthermore, "hsa-miR-4516" can be obtained by the method The miRBase Accession No. 1000012644444444 forms a hairpin-like structure. The sequence of the gene encoding the nucleotide sequence of the present invention is known to be nucleotide sequence no. MI0016882, sequence number 479.

[0211] As used herein, "hsa-miR-4649-5p gene" or "hsa-mi The term "miR-4649-5p" refers to hsa-miR-4649 set forth in SEQ ID NO: 467. -5p gene (miRBase Accession No. MIMAT0019711 ) and other species homologs or orthologs. The 49-5p gene is described in Persson H et al., 2011, Cancer Res., 7 It can be obtained by the method described in Vol. 1, pp. 78-86. R-4649-5p is a precursor of hsa-mir-4, which has a hairpin-like structure. 649" (miRBase Accession No. MI0017276, SEQ ID NO: 480) is known.

[0212] As used herein, "hsa-miR-760 gene" or "hsa-miR-76 The term "miR-760" refers to the hsa-miR-760 gene (miRBa se Accession No. MIMAT0004957) and other species homologs The hsa-miR-760 gene is a member of the Berezi kov E et al., 2006, Genome Res., Vol. 16, p289-1298 hsa-miR-760 can be obtained by the method described in the literature. The miRBase Accelerator, "hsa-mir-760" (miRBase Accelerator), has a hairpin-like structure. Session No. MI0005567, SEQ ID NO: 481) is known.

[0213] As used herein, "hsa-miR-3162-5p gene" or "hsa-mi The term "miR-3162-5p" refers to hsa-miR-3162 set forth in SEQ ID NO: 469. -5p gene (miRBase Accession No. MIMAT0015036 ) and other species homologs or orthologs. The 62-5p gene is Stark MS et al., 2010, PLoS One., Vol. 5, e The miR-316 can be obtained by the method described in 9685. 2-5p" has a hairpin-like structure as its precursor "hsa-mir-3162" ( miRBase Accession No. MI0014192, SEQ ID NO: 482) It is known.

[0214] As used herein, "hsa-miR-3178 gene" or "hsa-miR-3 The term "miR-3178" refers to the hsa-miR-3178 gene (miR-3178) set forth in SEQ ID NO: 470. RBase Accession No. MIMAT0015055) and other species The hsa-miR-3178 gene is a homologue or ortholog of the St The method described in ark MS et al., 2010, PLoS One., Vol. 5, e9685 Furthermore, "hsa-miR-3178" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-3178" (miRBase Accession No. on No. MI0014212, SEQ ID NO: 483) is known.

[0215] As used herein, "hsa-miR-940 gene" or "hsa-miR-94 The term "miR-940" refers to the hsa-miR-940 gene (miRBa se Accession No. MIMAT0004983) and other species homologs The hsa-miR-940 gene is a gene encoding miR-940. et al., 2007, Cancer Res., Vol. 67, pp. 6031-6043 hsa-miR-940 can be obtained by the method described above. The miRBase Accession No. 100001266666 (hsa-mir-940) forms a hairpin-like structure. on No. MI0005762, SEQ ID NO: 484) is known.

[0216] As used herein, "hsa-miR-4271 gene" or "hsa-miR-4 The term "miR-4271" refers to the hsa-miR-4271 gene (miR-4271) set forth in SEQ ID NO: 472. RBase Accession No. MIMAT0016901) and other species The hsa-miR-4271 gene is a homologue or ortholog. The method described in ff LA et al., 2009, PLoS One., Vol. 4, e7192 hsa-miR-4271 can be obtained as a precursor. The miRBase Accession No. hsa-mir-4271 (miRBase Accession No. hsa-mir-4271) has an apin-like structure. n No. MI0015879, sequence number 485) is known.

[0217] As used herein, "hsa-miR-6769b-5p gene" or "hsa-m The term "miR-6769b-5p" refers to hsa-miR-6769b-5p as set forth in SEQ ID NO: 473. 69b-5p gene (miRBase Accession No. MIMAT0027 620) and other species homologs or orthologs. The -6769b-5p gene is from Ladewig E et al., 2012, Genome Re It can be obtained by the method described in Vol. 22, pp. 1634-1645. "hsa-miR-6769b-5p" has a hairpin-like structure as its precursor " hsa-mir-6769b” (miRBase Accession No. MI00 22706, SEQ ID NO: 486) is known.

[0218] As used herein, "hsa-miR-4508 gene" or "hsa-miR-4 The term "miR-4508" refers to the hsa-miR-4508 gene (miR-4508) set forth in SEQ ID NO: 474. RBase Accession No. MIMAT0019045) and other species The hsa-miR-4508 gene is a homologue or ortholog. Ma DD et al., 2010, Blood., Vol. 116, e118-e127 Furthermore, "hsa-miR-4508" can be obtained by the method described above. The miRBase Accession No. 1006266666, which forms a hairpin-like structure, is sion No. MI0016872, SEQ ID NO: 487) is known.

[0219] As used herein, "hsa-miR-6826-5p gene" or "hsa-mi The term "miR-6826-5p" refers to hsa-miR-6826 set forth in SEQ ID NO: 475. -5p gene (miRBase Accession No. MIMAT0027552 ) and other species homologs or orthologs. The 26-5p gene is described in Ladewig E et al., 2012, Genome Res., 2 It can be obtained by the method described in Vol. 2, pp. 1634-1645. a-miR-6826-5p has a hairpin-like structure as its precursor, hsa-m ir-6826” (miRBase Accession No. MI0022671, SEQ ID NO: 488) is known.

[0220] As used herein, "hsa-miR-6757-5p gene" or "hsa-mi The term "miR-6757-5p" refers to hsa-miR-6757 as set forth in SEQ ID NO: 476. -5p gene (miRBase Accession No. MIMAT0027414 ) and other species homologs or orthologs. The 57-5p gene is described in Ladewig E et al., 2012, Genome Res., 2 It can be obtained by the method described in Vol. 2, pp. 1634-1645. a-miR-6757-5p has a hairpin-like structure as its precursor, hsa-m ir-6757” (miRBase Accession No. MI0022602, SEQ ID NO: 489) is known.

[0221] As used herein, "hsa-miR-3131 gene" or "hsa-miR-3 The term "miR-3131" refers to the hsa-miR-3131 gene (miR-3131) set forth in SEQ ID NO: 477. RBase Accession No. MIMAT0014996) and other species The hsa-miR-3131 gene is a homologue or ortholog of the St The method described in ark MS et al., 2010, PLoS One., Vol. 5, e9685 In addition, "hsa-miR-3131" can be obtained as its precursor. The hairpin-like structure of "hsa-mir-3131" (miRBase Accession No. on No. MI0014151, SEQ ID NO: 490) is known.

[0222] As used herein, "hsa-miR-1343-3p gene" or "hsa-mi The term "miR-1343-3p" refers to hsa-miR-1343 as set forth in SEQ ID NO: 478. -3p gene (miRBase Accession No. MIMAT0019776 ) and other species homologs or orthologs. The 43-3p gene is described in Persson H et al., 2011, Cancer Res., 7 It can be obtained by the method described in Vol. 1, pp. 78-86. R-1343-3p is a precursor of hsa-mir-1, which has a hairpin-like structure. 343" (miRBase Accession No. MI0017320, SEQ ID NO: 491) is known.

[0223] In addition, mature miRNAs are formed from RNA precursors with hairpin-like structures. When excised as A, one to several bases before and after the sequence may be excised shorter or longer, Base substitutions can occur, resulting in mutants, called isomiRs (Morin R D. et al., 2008, Genome Research, Vol. 18, pp. 610-621 In miRBase Release 20, SEQ ID NOs: 1 to 148, 466 to 478 In addition to the base sequences represented by either of these, there are numerous isomiRs, such as those represented by SEQ ID NOs: 300 to 309. Variants and fragments of the nucleotide sequences represented by either 465 and 492-509 are also shown. These mutants are also represented by any of SEQ ID NOs: 1 to 148, 466 to 478. It can be obtained as miRNA having a base sequence.

[0224] That is, SEQ ID NOs: 1, 3, 4, 6, 14, 16, 17, 18, 22, 23, 24, 25, 30, 31, 34, 35, 37, 42, 43, 44, 47, 48, 49, 5 0, 51, 52, 55, 57, 59, 61, 62, 66, 67, 69, 70, 72, 73 , 75, 77, 79, 80, 82, 83, 84, 85, 86, 89, 90, 92, 94, 96, 99, 101, 102, 103, 104, 106, 107, 109, 110, 11 1, 112, 113, 115, 116, 120, 121, 122, 124, 130, 13 1, 132, 133, 136, 137, 138, 139, 140, 141, 142, 14 4, 146, 147, 466, 467, 468, 469, 470, 471, 474, 47 7, and a base sequence represented by 478, or a base sequence in which u is replaced by t Among the variants of the polynucleotide consisting of, for example, miRBase Release The longest variants registered in 20 are SEQ ID NOs: 300, 302, and 304, respectively. , 306, 308, 310, 312, 314, 316, 318, 320, 322, 324 , 326, 328, 330, 332, 334, 336, 338, 340, 342, 344 , 346, 348, 350, 352, 354, 356, 358, 360, 362, 364 , 366, 368, 370, 372, 374, 376, 378, 380, 382, ​​384 , 386, 388, 390, 392, 394, 396, 398, 400, 402, 404 , 406, 408, 410, 412, 414, 416, 418, 420, 422, 424 , 426, 428, 430, 432, 434, 436, 438, 440, 442, 444 , 446, 448, 450, 452, 454, 456, 458, 460, 462, 464 ,492, 494, 496, 498, 500, 502, 504, 506, and ,508 Examples include polynucleotides represented by the following:

[0225] In addition, SEQ ID NOs: 1, 3, 4, 6, 14, 16, 17, 18, 22, 23, 24 of the present invention , 25, 30, 31, 34, 35, 37, 42, 43, 44, 47, 48, 49, 50, 51, 52, 55, 57, 59, 61, 62, 66, 67, 69, 70, 72, 73, 7 5, 77, 79, 80, 82, 83, 84, 85, 86, 89, 90, 92, 94, 96 , 99, 101, 102, 103, 104, 106, 107, 109, 110, 111, 112, 113, 115, 116, 120, 121, 122, 124, 130, 131, 132, 133, 136, 137, 138, 139, 140, 141, 142, 144, 146, 147, 466, 467, 468, 469, 470, 471, 474, 477, and from the base sequence represented by 478 or the base sequence in which u is t For example, the variants of the polynucleotides The shortest variants registered in the database are SEQ ID NOs: 301, 303, 305, and 3 07, 309, 311, 313, 315, 317, 319, 321, 323, 325, 3 27, 329, 331, 333, 335, 337, 339, 341, 343, 345, 3 47, 349, 351, 353, 355, 357, 359, 361, 363, 365, 3 67, 369, 371, 373, 375, 377, 379, 381, 383, 385, 3 87, 389, 391, 393, 395, 397, 399, 401, 403, 405, 4 07, 409, 411, 413, 415, 417, 419, 421, 423, 425, 4 27, 429, 431, 433, 435, 437, 439, 441, 443, 445, 4 47, 449, 451, 453, 455, 457, 459, 461, 463, 465, 4 93, 495, 497, 499, 501, 503, 505, 507, and 509 In addition to these variants and fragments, polynucleotides of m Sequence numbers 1, 3, 4, 6, 14, 16, 17, 18, and 22 registered in iRBase 23, 24, 25, 30, 31, 34, 35, 37, 42, 43, 44, 47, 48, 4 9, 50, 51, 52, 55, 57, 59, 61, 62, 66, 67, 69, 70, 72 , 73, 75, 77, 79, 80, 82, 83, 84, 85, 86, 89, 90, 92, 94, 96, 99, 101, 102, 103, 104, 106, 107, 109, 110 , 111, 112, 113, 115, 116, 120, 121, 122, 124, 130 , 131, 132, 133, 136, 137, 138, 139, 140, 141, 142 , 144, 146, and 147 are polynucleotides that are isomiRs. Furthermore, a polypeptide containing a base sequence represented by any one of SEQ ID NOs: 1 to 148, 466 to 478 Examples of oligonucleotides include the precursors SEQ ID NOS: 149-299 and 479, respectively. Examples of the polynucleotide include those represented by any one of the following:

[0226] Names of genes represented by SEQ ID NOs: 1 to 509 and miRBase Accession Numbers The registration numbers are listed in Table 1.

[0227] As used herein, the term "capable of specifically binding" refers to the nucleic acid probe or probe used in the present invention. This means that the primer binds to a specific target nucleic acid and is substantially incapable of binding to other nucleic acids. .

[0228] [Table 1] TIFF2025138727000002.tif249121TIFF2025138727000003.tif249135TIFF2025138727000004.tif255124TIFF2025138727 000005.tif252120TIFF2025138727000006.tif251131TIFF2025138727000007.tif248149TIFF2025138727000008.tif24912 5TIFF2025138727000009.tif249142TIFF2025138727000010.tif254126TIFF2025138727000011.tif253125TIFF2025138727 000012.tif254133TIFF2025138727000013.tif252127TIFF2025138727000014.tif248114TIFF2025138727000015.tif56119

[0229] This specification is a joint publication of Japanese Patent Application Nos. 2014-120884 and 2014-1857, which are priority documents of the present application. This includes the contents described in the specification and drawings of Patent No. 33. [Effects of the Invention]

[0230] The present invention makes it possible to detect biliary tract cancer easily and with high accuracy. refers to measurements of several miRNAs in patients' blood, serum, and / or plasma that can be collected minimally invasively. This can be used as a target to easily detect whether a patient has biliary tract cancer. [Brief explanation of the drawings]

[0231] [Figure 1] This figure shows the relationship between the base sequences of hsa-miR-4665-5p, represented by sequence number 51, and hsa-miR-4665-3p, represented by sequence number 91, which are generated from the precursor hsa-mir-4665, represented by sequence number 201. [Figure 2]Left: The vertical axis shows the measured values ​​of hsa-miR-125a-3p (SEQ ID NO: 1) in healthy subjects (100 individuals) and biliary tract cancer patients (67 individuals) selected as the training sample group. The horizontal line in the figure indicates the threshold (5.69) optimized by Fisher's discriminant analysis to distinguish between the two groups. Right: The vertical axis shows the measured values ​​of hsa-miR-125a-3p (SEQ ID NO: 1) in healthy subjects (50 individuals) and biliary tract cancer patients (33 individuals) selected as the test sample group. The horizontal line in the figure indicates the threshold (5.69) set in the training sample group to distinguish between the two groups. [Figure 3] Left: The horizontal axis shows the measured values ​​of hsa-miR-6893-5p (SEQ ID NO: 2) and the vertical axis shows the measured values ​​of hsa-miR-4476 (SEQ ID NO: 4) for healthy individuals (100 individuals, circles) and biliary tract cancer patients (67 individuals, triangles) selected as the training sample group. The line in the figure represents the discriminant function (0 = 5.16x + y + 48.11) for discriminating between the two groups, optimized by Fisher's discriminant analysis. Right: The horizontal axis shows the measured values ​​of hsa-miR-6893-5p (SEQ ID NO: 2) and the vertical axis shows the measured values ​​of hsa-miR-4476 (SEQ ID NO: 4) for healthy individuals (50 individuals, circles) and biliary tract cancer patients (33 individuals, triangles) selected as the test sample group. The line in the figure represents the threshold (0 = 5.16x + y + 48.11) for discriminating between the two groups, set in the training sample group. [Figure 4]Upper figure: hsa-miR-6075 (SEQ ID NO: 15), hsa-miR-6836-3p (SEQ ID NO: 12), hsa-miR-6799-5p (SEQ ID NO: 29), and hsa-miR-125a in 67 biliary tract cancer patients, 93 healthy subjects, 35 colorectal cancer patients, 37 gastric cancer patients, 32 esophageal cancer patients, 38 liver cancer patients, and 13 patients with benign pancreatic and biliary diseases selected as the learning sample group. A discriminant equation was created using Fisher's discriminant analysis from the measured values ​​of -3p (SEQ ID NO: 1) (-1.25 × hsa-miR-6075 − 1.06 × hsa-miR-6836-3p + 0.53 × hsa-miR-6799-5p + 0.18 × hsa-miR-125a-3p + 15.41), and the discriminant score obtained from the discriminant equation is plotted on the vertical axis and the sample group on the horizontal axis. The dotted line in the figure indicates the discriminant boundary for discriminating between the two groups, where the discriminant score is 0. The figure below shows the measured values ​​of hsa-miR-6075 (SEQ ID NO: 15), hsa-miR-6836-3p (SEQ ID NO: 12), hsa-miR-6799-5p (SEQ ID NO: 29), and hsa-miR-125a-3p (SEQ ID NO: 1) for the test sample group: 33 biliary tract cancer patients, 57 healthy subjects, 15 colorectal cancer patients, 13 gastric cancer patients, 18 esophageal cancer patients, 12 liver cancer patients, and 8 patients with benign pancreatic and biliary diseases. The discriminant scores obtained from the discriminant equation for the training sample group are plotted on the vertical axis, and the sample group is plotted on the horizontal axis. The dotted line in the figure indicates the discriminant boundary for distinguishing between the two groups, where the discriminant score is 0. DETAILED DESCRIPTION OF THE INVENTION

[0232] The present invention will be explained in more detail below. 1. Target nucleic acid for biliary tract cancer The nucleic acid probe or primer for detecting biliary tract cancer defined above according to the present invention is used to detect biliary tract cancer. as a biliary tract cancer marker for detecting the presence and / or absence of biliary tract cancer or biliary tract cancer cells The main target nucleic acids of miR-125a-3p, miR-6893- 5p, hsa-miR-204-3p, hsa-miR-4476, hsa-miR-4 294、hsa-miR-150-3p、hsa-miR-6729-5p、hsa-m iR-7641、hsa-miR-6765-3p、hsa-miR-6820-5p、 hsa-miR-575, hsa-miR-6836-3p, hsa-miR-1469 、hsa-miR-663a、hsa-miR-6075、hsa-miR-4634、 hsa-miR-423-5p, hsa-miR-4454, hsa-miR-7109 -5p、hsa-miR-6789-5p、hsa-miR-6877-5p、hsa- miR-4792, hsa-miR-4530, hsa-miR-7975, hsa-m iR-6724-5p、hsa-miR-8073、hsa-miR-7977、hsa -miR-1231、hsa-miR-6799-5p、hsa-miR-615-5p hsa-miR-4450, hsa-miR-6726-5p, hsa-miR-68 75-5p、hsa-miR-4734、hsa-miR-16-5p、hsa-miR -602、hsa-miR-4651、hsa-miR-8069、hsa-miR-1 238-5p、hsa-miR-6880-5p、hsa-miR-8072、hsa- miR-4723-5p、hsa-miR-4732-5p、hsa-miR-6125 hsa-miR-6090, hsa-miR-7114-5p, hsa-miR-56 4, hsa-miR-451a, hsa-miR-3135b, hsa-miR-449 7、hsa-miR-4665-5p、hsa-miR-3622a-5p、hsa-m iR-6850-5p、hsa-miR-6821-5p、hsa-miR-5100、 hsa-miR-6872-3p、hsa-miR-4433-3p、hsa-miR- 1227-5p、hsa-miR-3188、hsa-miR-7704、hsa-mi R-3185、hsa-miR-1908-3p、hsa-miR-6781-5p、h sa-miR-6805-5p、hsa-miR-8089、hsa-miR-665、 hsa-miR-4486, hsa-miR-6722-3p, hsa-miR-126 0a、hsa-miR-4707-5p、hsa-miR-6741-5p、hsa-m iR-1260b、hsa-miR-1246、hsa-miR-6845-5p、hs a-miR-4638-5p、hsa-miR-6085、hsa-miR-1228- 3p、hsa-miR-4534、hsa-miR-5585-3p、hsa-miR- 4741、hsa-miR-4433b-3p、hsa-miR-197-5p、hsa -miR-718、hsa-miR-4513、hsa-miR-4446-3p、hs a-miR-619-5p、hsa-miR-6816-5p、hsa-miR-677 8-5p、hsa-miR-24-3p、hsa-miR-1915-3p、hsa-m iR-4665-3p、hsa-miR-4449、hsa-miR-6889-5p、 hsa-miR-486-3p、hsa-miR-7113-3p、hsa-miR-6 42a-3p、hsa-miR-7847-3p、hsa-miR-6768-5p、h sa-miR-1290、hsa-miR-7108-5p、hsa-miR-92b- 5p、hsa-miR-663b、hsa-miR-3940-5p、hsa-miR- 4467、hsa-miR-6858-5p、hsa-miR-4417、hsa-mi R-3665, hsa-miR-4736, hsa-miR-4687-3p, hsa- miR-1908-5p, hsa-miR-5195-3p, hsa-miR-4286 , hsa-miR-3679-3p, hsa-miR-6791-5p, hsa-miR -1202, hsa-miR-3656, hsa-miR-4746-3p, hsa-m iR-3184-5p, hsa-miR-3937, hsa-miR-6515-3p, hsa-miR-6132, hsa-miR-187-5p, hsa-miR-7111 -5p, hsa-miR-5787, hsa-miR-6779-5p, hsa-miR -4516, hsa-miR-4649-5p, hsa-miR-760, hsa-mi R-3162-5p, hsa-miR-3178, hsa-miR-940, hsa-m iR-4271, hsa-miR-6769b-5p, hsa-miR-4508, hs a-miR-6826-5p, hsa-miR-6757-5p, hsa-miR-31 31, and at least one selected from the group consisting of hsa-miR-1343-3p The above miRNAs can be used. Furthermore, by combining these miRNAs Other biliary tract cancer markers that can be used include hsa-miR-6808-5p, hsa- miR-6774-5p, hsa-miR-4656, hsa-miR-6806-5p , hsa-miR-1233-5p, hsa-miR-328-5p, hsa-miR- 4674, hsa-miR-2110, hsa-miR-6076, hsa-miR-3 619-3p, hsa-miR-92a-2-5p, hsa-miR-128-1-5p , hsa-miR-638, hsa-miR-2861, hsa-miR-371a-5 p, hsa-miR-211-3p, hsa-miR-1273g-3p, hsa-mi R-1203, hsa-miR-122-5p, hsa-miR-4258, hsa-m from iR-4484, hsa-miR-4648 and hsa-miR-6780b-5p At least one miRNA selected from the group consisting of: It is possible.

[0233] The above miRNAs include, for example, those represented by any of SEQ ID NOs: 1 to 148, 466 to 478. Human genes containing the base sequence that is involved in the p, hsa-miR-6893-5p, hsa-miR-204-3p, hsa-miR -4476, hsa-miR-4294, hsa-miR-150-3p, hsa-mi R-6729-5p, hsa-miR-7641, hsa-miR-6765-3p, h sa-miR-6820-5p, hsa-miR-575, hsa-miR-6836- 3p, hsa-miR-1469, hsa-miR-663a, hsa-miR-607 5, hsa-miR-4634, hsa-miR-423-5p, hsa-miR-44 54, hsa-miR-7109-5p, hsa-miR-6789-5p, hsa-m iR-6877-5p, hsa-miR-4792, hsa-miR-4530, hsa -miR-7975, hsa-miR-6724-5p, hsa-miR-8073, h sa-miR-7977, hsa-miR-1231, hsa-miR-6799-5p , hsa-miR-615-5p, hsa-miR-4450, hsa-miR-672 6-5p, hsa-miR-6875-5p, hsa-miR-4734, hsa-mi R-16-5p、hsa-miR-602、hsa-miR-4651、hsa-miR -8069、hsa-miR-1238-5p、hsa-miR-6880-5p、hs a-miR-8072、hsa-miR-4723-5p、hsa-miR-4732- 5p、hsa-miR-6125、hsa-miR-6090、hsa-miR-711 4-5p、hsa-miR-564、hsa-miR-451a、hsa-miR-31 35b、hsa-miR-4497、hsa-miR-4665-5p、hsa-miR -3622a-5p、hsa-miR-6850-5p、hsa-miR-6821-5 p、hsa-miR-5100、hsa-miR-6872-3p、hsa-miR-4 433-3p、hsa-miR-1227-5p、hsa-miR-3188、hsa- miR-7704, hsa-miR-3185, hsa-miR-1908-3p, hs a-miR-6781-5p、hsa-miR-6805-5p、hsa-miR-80 89, hsa-miR-665, hsa-miR-4486, hsa-miR-6722 -3p、hsa-miR-1260a、hsa-miR-4707-5p、hsa-mi R-6741-5p、hsa-miR-1260b、hsa-miR-1246、hsa -miR-6845-5p、hsa-miR-4638-5p、hsa-miR-608 5, hsa-miR-1228-3p, hsa-miR-4534, hsa-miR-5 585-3p、hsa-miR-4741、hsa-miR-4433b-3p、hsa -miR-197-5p、hsa-miR-718、hsa-miR-4513、hsa -miR-4446-3p、hsa-miR-619-5p、hsa-miR-6816 -5p、hsa-miR-6778-5p、hsa-miR-24-3p、hsa-mi R-1915-3p、hsa-miR-4665-3p、hsa-miR-4449、h sa-miR-6889-5p、hsa-miR-486-3p、hsa-miR-71 13-3p、hsa-miR-642a-3p、hsa-miR-7847-3p、hs a-miR-6768-5p、hsa-miR-1290、hsa-miR-7108- 5p、hsa-miR-92b-5p、hsa-miR-663b、hsa-miR-3 940-5p、hsa-miR-4467、hsa-miR-6858-5p、hsa- miR-4417, hsa-miR-3665, hsa-miR-4736, hsa-m iR-4687-3p、hsa-miR-1908-5p、hsa-miR-5195- 3p、hsa-miR-4286、hsa-miR-3679-3p、hsa-miR- 6791-5p、hsa-miR-1202、hsa-miR-3656、hsa-mi R-4746-3p、hsa-miR-3184-5p、hsa-miR-3937、h sa-miR-6515-3p、hsa-miR-6132、hsa-miR-187- 5p、hsa-miR-7111-5p、hsa-miR-5787、hsa-miR- 6779-5p、hsa-miR-6808-5p、hsa-miR-6774-5p、 hsa-miR-4656, hsa-miR-6806-5p, hsa-miR-123 3-5p、hsa-miR-328-5p、hsa-miR-4674、hsa-miR -2110、hsa-miR-6076、hsa-miR-3619-3p、hsa-m iR-92a-2-5p, hsa-miR-128-1-5p, hsa-miR-638 , hsa-miR-2861, hsa-miR-371a-5p, hsa-miR-21 1-3p, hsa-miR-1273g-3p, hsa-miR-1203, hsa-m iR-122-5p, hsa-miR-4258, hsa-miR-4484, hsa- miR-4648, hsa-miR-6780b-5p, hsa-miR-4516, h sa-miR-4649-5p, hsa-miR-760, hsa-miR-3162- 5p, hsa-miR-3178, hsa-miR-940, hsa-miR-4271 , hsa-miR-6769b-5p, hsa-miR-4508, hsa-miR-6 826-5p, hsa-miR-6757-5p, hsa-miR-3131, and h sa-miR-1343-3p), its homologs, its transcripts, and its mutants or derivatives Here, genes, homologs, transcripts, variants and derivatives are defined as above. This is the case.

[0234] A preferred target nucleic acid is a human gene comprising a base sequence represented by any one of SEQ ID NOs: 1 to 509. A gene or its transcription product, more preferably, the transcription product, i.e., miRNA, The miRNA is a precursor RNA of the miRNA, pri-miRNA or pre-miRNA.

[0235] The first target gene is the hsa-miR-125a-3p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0236] The second target gene is the hsa-miR-6893-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0237] The third target gene is the hsa-miR-204-3p gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0238] The fourth target gene is the hsa-miR-4476 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0239] The fifth target gene is the hsa-miR-4294 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0240] The sixth target gene is the hsa-miR-150-3p gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0241] The seventh target gene is the hsa-miR-6729-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0242] The eighth target gene is the hsa-miR-7641 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0243] The ninth target gene is the hsa-miR-6765-3p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0244] The tenth target gene is the hsa-miR-6820-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0245] The eleventh target gene is the hsa-miR-575 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0246] The 12th target gene is the hsa-miR-6836-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0247] The 13th target gene is the hsa-miR-1469 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0248] The 14th target gene is the hsa-miR-663a gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0249] The 15th target gene is the hsa-miR-6075 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0250] The 16th target gene is the hsa-miR-4634 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0251] The 17th target gene is the hsa-miR-423-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0252] The 18th target gene is the hsa-miR-4454 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0253] The 19th target gene is the hsa-miR-7109-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0254] The 20th target gene is the hsa-miR-6789-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0255] The 21st target gene is the hsa-miR-6877-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0256] The 22nd target gene is the hsa-miR-4792 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0257] The 23rd target gene is the hsa-miR-4530 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0258] The 24th target gene is the hsa-miR-7975 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0259] The 25th target gene is the hsa-miR-6724-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0260] The 26th target gene is the hsa-miR-8073 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0261] The 27th target gene is the hsa-miR-7977 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0262] The 28th target gene is the hsa-miR-1231 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0263] The 29th target gene is the hsa-miR-6799-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0264] The 30th target gene is the hsa-miR-615-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0265] The 31st target gene is the hsa-miR-4450 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0266] The 32nd target gene is the hsa-miR-6726-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0267] The 33rd target gene is the hsa-miR-6875-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0268] The 34th target gene is the hsa-miR-4734 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0269] The 35th target gene is the hsa-miR-16-5p gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0270] The 36th target gene is the hsa-miR-602 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0271] The 37th target gene is the hsa-miR-4651 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0272] The 38th target gene is the hsa-miR-8069 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0273] The 39th target gene is the hsa-miR-1238-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0274] The 40th target gene is the hsa-miR-6880-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0275] The 41st target gene is the hsa-miR-8072 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0276] The 42nd target gene is the hsa-miR-4723-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0277] The 43rd target gene is the hsa-miR-4732-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0278] The 44th target gene is the hsa-miR-6125 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0279] The 45th target gene is the hsa-miR-6090 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0280] The 46th target gene is the hsa-miR-7114-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0281] The 47th target gene is the hsa-miR-564 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0282] The 48th target gene is the hsa-miR-451a gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0283] The 49th target gene is the hsa-miR-3135b gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0284] The 50th target gene is the hsa-miR-4497 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0285] The 51st target gene is the hsa-miR-4665-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0286] The 52nd target gene is the hsa-miR-3622a-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0287] The 53rd target gene is the hsa-miR-6850-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0288] The 54th target gene is the hsa-miR-6821-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0289] The 55th target gene is the hsa-miR-5100 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0290] The 56th target gene is the hsa-miR-6872-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0291] The 57th target gene is the hsa-miR-4433-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0292] The 58th target gene is the hsa-miR-1227-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0293] The 59th target gene is the hsa-miR-3188 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0294] The 60th target gene is the hsa-miR-7704 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0295] The 61st target gene is the hsa-miR-3185 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0296] The 62nd target gene is the hsa-miR-1908-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0297] The 63rd target gene is the hsa-miR-6781-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0298] The 64th target gene is the hsa-miR-6805-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0299] The 65th target gene is the hsa-miR-8089 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0300] The 66th target gene is the hsa-miR-665 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0301] The 67th target gene is the hsa-miR-4486 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0302] The 68th target gene is the hsa-miR-6722-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0303] The 69th target gene is the hsa-miR-1260a gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0304] The 70th target gene is the hsa-miR-4707-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0305] The 71st target gene is the hsa-miR-6741-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0306] The 72nd target gene is the hsa-miR-1260b gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0307] The 73rd target gene is the hsa-miR-1246 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0308] The 74th target gene is the hsa-miR-6845-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0309] The 75th target gene is the hsa-miR-4638-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0310] The 76th target gene is the hsa-miR-6085 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0311] The 77th target gene is the hsa-miR-1228-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0312] The 78th target gene is the hsa-miR-4534 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0313] The 79th target gene is the hsa-miR-5585-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0314] The 80th target gene is the hsa-miR-4741 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0315] The 81st target gene is the hsa-miR-4433b-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0316] The 82nd target gene is the hsa-miR-197-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0317] The 83rd target gene is the hsa-miR-718 gene, its homologs, and their transcription factors. The gene or its transcript, or a variant or derivative thereof, has not been There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0318] The 84th target gene is the hsa-miR-4513 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0319] The 85th target gene is the hsa-miR-4446-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0320] The 86th target gene is the hsa-miR-619-5p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0321] The 87th target gene is the hsa-miR-6816-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0322] The 88th target gene is the hsa-miR-6778-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0323] The 89th target gene is the hsa-miR-24-3p gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0324] The 90th target gene is the hsa-miR-1915-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0325] The 91st target gene is the hsa-miR-4665-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0326] The 92nd target gene is the hsa-miR-4449 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0327] The 93rd target gene is the hsa-miR-6889-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0328] The 94th target gene is the hsa-miR-486-3p gene, its homologs, and The gene is a transcription product of the gene, or a variant or derivative thereof. There are no known reports that altered transcript expression can be a marker for biliary tract cancer.

[0329] The 95th target gene is the hsa-miR-7113-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0330] The 96th target gene is the hsa-miR-642a-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0331] The 97th target gene is the hsa-miR-7847-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0332] The 98th target gene is the hsa-miR-6768-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0333] The 99th target gene is the hsa-miR-1290 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0334] The 100th target gene is the hsa-miR-7108-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0335] The 101st target gene is the hsa-miR-92b-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0336] The 102nd target gene is the hsa-miR-663b gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0337] The 103rd target gene is the hsa-miR-3940-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0338] The 104th target gene is the hsa-miR-4467 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0339] The 105th target gene is the hsa-miR-6858-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0340] The 106th target gene is the hsa-miR-4417 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0341] The 107th target gene is the hsa-miR-3665 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0342] The 108th target gene is the hsa-miR-4736 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0343] The 109th target gene is the hsa-miR-4687-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0344] The 110th target gene is the hsa-miR-1908-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0345] The 111th target gene is the hsa-miR-5195-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0346] The 112th target gene is the hsa-miR-4286 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0347] The 113th target gene is the hsa-miR-3679-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0348] The 114th target gene is the hsa-miR-6791-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0349] The 115th target gene is the hsa-miR-1202 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0350] The 116th target gene is the hsa-miR-3656 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0351] The 117th target gene is the hsa-miR-4746-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0352] The 118th target gene is the hsa-miR-3184-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0353] The 119th target gene is the hsa-miR-3937 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0354] The 120th target gene is the hsa-miR-6515-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0355] The 121st target gene is the hsa-miR-6132 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0356] The 122nd target gene is the hsa-miR-187-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0357] The 123rd target gene is the hsa-miR-7111-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0358] The 124th target gene is the hsa-miR-5787 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0359] The 125th target gene is the hsa-miR-6779-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0360] The 126th target gene is the hsa-miR-6808-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0361] The 127th target gene is the hsa-miR-6774-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0362] The 128th target gene is the hsa-miR-4656 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0363] The 129th target gene is the hsa-miR-6806-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0364] The 130th target gene is the hsa-miR-1233-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0365] The 131st target gene is the hsa-miR-328-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0366] The 132nd target gene is the hsa-miR-4674 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0367] The 133rd target gene is the hsa-miR-2110 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0368] The 134th target gene is the hsa-miR-6076 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0369] The 135th target gene is the hsa-miR-3619-3p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0370] The 136th target gene is the hsa-miR-92a-2-5p gene and its homologs , their transcription products, or their mutants or derivatives. However, there are no reports that altered expression of its transcripts can be a marker for biliary tract cancer. stomach.

[0371] The 137th target gene is the hsa-miR-128-1-5p gene and its homologs , their transcription products, or their mutants or derivatives. However, there are no reports that altered expression of its transcripts can be a marker for biliary tract cancer. stomach.

[0372] The 138th target gene is the hsa-miR-638 gene, its homologs, and their The gene or its transcription product, or a variant or derivative thereof. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0373] The 139th target gene is the hsa-miR-2861 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0374] The 140th target gene is the hsa-miR-371a-5p gene, its homologs, The gene is a transcription product thereof, or a variant or derivative thereof. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0375] The 141st target gene is the hsa-miR-211-3p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0376] The 142nd target gene is the hsa-miR-1273g-3p gene and its homologs , their transcription products, or their mutants or derivatives. However, there are no reports that altered expression of its transcripts can be a marker for biliary tract cancer. stomach.

[0377] The 143rd target gene is the hsa-miR-1203 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0378] The 144th target gene is the hsa-miR-122-5p gene, its homologs, and These are transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0379] The 145th target gene is the hsa-miR-4258 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0380] The 146th target gene is the hsa-miR-4484 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0381] The 147th target gene is the hsa-miR-4648 gene, its homologs, and their The gene or its transcription product, or its variant or derivative. There are no known reports suggesting that altered transcript expression can be a marker for biliary tract cancer.

[0382] The 148th target gene is the hsa-miR-6780b-5p gene and its homologs , their transcription products, or their mutants or derivatives. However, there are no reports that altered expression of its transcripts can be a marker for biliary tract cancer. stomach.

[0383] The 149th target gene is the hsa-miR-4516 gene, its homologs, and their or their variants or derivatives. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0384] The 150th target gene is the hsa-miR-4649-5p gene, its homologs, The genes or their transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0385] The 151st target gene is the hsa-miR-760 gene, its homologs, and their The gene or its transcript, or a variant or derivative thereof. There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0386] The 152nd target gene is the hsa-miR-3162-5p gene, its homologs, The genes or their transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0387] The 153rd target gene is the hsa-miR-3178 gene, its homologs, and their or their variants or derivatives. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0388] The 154th target gene is the hsa-miR-940 gene, its homologs, and their The gene or its transcript, or a variant or derivative thereof. There are no known reports that altered expression of these proteins could be markers for biliary tract cancer.

[0389] The 155th target gene is the hsa-miR-4271 gene, its homologs, and their or their variants or derivatives. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0390] The 156th target gene is the hsa-miR-6769b-5p gene and its homologs , their transcription products, or their variants or derivatives. There are no known reports that altered expression of this transcript could be a marker for biliary tract cancer. .

[0391] The 157th target gene is the hsa-miR-4508 gene, its homologs, and their or their variants or derivatives. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0392] The 158th target gene is the hsa-miR-6826-5p gene, its homologs, The genes or their transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0393] The 159th target gene is the hsa-miR-6757-5p gene, its homologs, The genes or their transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0394] The 160th target gene is the hsa-miR-3131 gene, its homologs, and their or their variants or derivatives. There are no known reports suggesting that changes in expression of these products could be markers for biliary tract cancer.

[0395] The 161st target gene is the hsa-miR-1343-3p gene, its homologs, The genes or their transcription products, or their variants or derivatives. There are no known reports suggesting that altered expression of this transcript could be a marker for biliary tract cancer.

[0396] 2. Nucleic acid probes or primers for detecting biliary tract cancer In the present invention, a nucleic acid capable of specifically binding to a target nucleic acid as the biliary tract cancer marker is The acid can be used as a nucleic acid, such as a nucleic acid probe or primer, for detecting or diagnosing biliary tract cancer. It can be used as such.

[0397] In the present invention, the method for detecting or diagnosing biliary tract cancer is Possible nucleic acid probes or primers include target nucleic acids such as the above-mentioned biliary tract cancer markers, e.g. For example, human-derived hsa-miR-125a-3p, hsa-miR-6893-5p, and h sa-miR-204-3p, hsa-miR-4476, hsa-miR-4294, hsa-miR-150-3p, hsa-miR-6729-5p, hsa-miR-7 641, hsa-miR-6765-3p, hsa-miR-6820-5p, hsa- miR-575, hsa-miR-6836-3p, hsa-miR-1469, hsa -miR-663a, hsa-miR-6075, hsa-miR-4634, hsa- miR-423-5p, hsa-miR-4454, hsa-miR-7109-5p, hsa-miR-6789-5p, hsa-miR-6877-5p, hsa-miR- 4792, hsa-miR-4530, hsa-miR-7975, hsa-miR-6 724-5p, hsa-miR-8073, hsa-miR-7977, hsa-miR -1231, hsa-miR-6799-5p, hsa-miR-615-5p, hsa -miR-4450, hsa-miR-6726-5p, hsa-miR-6875-5 p, hsa-miR-4734, hsa-miR-16-5p, hsa-miR-602 , hsa-miR-4651, hsa-miR-8069, hsa-miR-1238- 5p, hsa-miR-6880-5p, hsa-miR-8072, hsa-miR- 4723-5p、hsa-miR-4732-5p、hsa-miR-6125、hsa -miR-6090、hsa-miR-7114-5p、hsa-miR-564、hs a-miR-451a、hsa-miR-3135b、hsa-miR-4497、hs a-miR-4665-5p、hsa-miR-3622a-5p、hsa-miR-6 850-5p、hsa-miR-6821-5p、hsa-miR-5100、hsa- miR-6872-3p、hsa-miR-4433-3p、hsa-miR-1227 -5p、hsa-miR-3188、hsa-miR-7704、hsa-miR-31 85、hsa-miR-1908-3p、hsa-miR-6781-5p、hsa-m iR-6805-5p、hsa-miR-8089、hsa-miR-665、hsa- miR-4486, hsa-miR-6722-3p, hsa-miR-1260a, h sa-miR-4707-5p、hsa-miR-6741-5p、hsa-miR-1 260b、hsa-miR-1246、hsa-miR-6845-5p、hsa-mi R-4638-5p、hsa-miR-6085、hsa-miR-1228-3p、h sa-miR-4534, hsa-miR-5585-3p, hsa-miR-4741 hsa-miR-4433b-3p, hsa-miR-197-5p, hsa-miR -718、hsa-miR-4513、hsa-miR-4446-3p、hsa-mi R-619-5p、hsa-miR-6816-5p、hsa-miR-6778-5p hsa-miR-24-3p, hsa-miR-1915-3p, hsa-miR-4 665-3p、hsa-miR-4449、hsa-miR-6889-5p、hsa- miR-486-3p, hsa-miR-7113-3p, hsa-miR-642a- 3p, hsa-miR-7847-3p, hsa-miR-6768-5p, hsa-m iR-1290, hsa-miR-7108-5p, hsa-miR-92b-5p, h sa-miR-663b, hsa-miR-3940-5p, hsa-miR-4467 , hsa-miR-6858-5p, hsa-miR-4417, hsa-miR-36 65, hsa-miR-4736, hsa-miR-4687-3p, hsa-miR- 1908-5p, hsa-miR-5195-3p, hsa-miR-4286, hsa -miR-3679-3p, hsa-miR-6791-5p, hsa-miR-120 2, hsa-miR-3656, hsa-miR-4746-3p, hsa-miR-3 184-5p, hsa-miR-3937, hsa-miR-6515-3p, hsa- miR-6132, hsa-miR-187-5p, hsa-miR-7111-5p, hsa-miR-5787, hsa-miR-6779-5p, hsa-miR-451 6, hsa-miR-4649-5p, hsa-miR-760, hsa-miR-31 62-5p, hsa-miR-3178, hsa-miR-940, hsa-miR-4 271, hsa-miR-6769b-5p, hsa-miR-4508, hsa-mi R-6826-5p, hsa-miR-6757-5p, hsa-miR-3131, young or hsa-miR-1343-3p or a combination thereof, or a homolog thereof , their transcription products, their variants or derivatives, and optionally combinations thereof. Can be combined, hsa-miR-6808-5p, hsa-miR-6774- 5p, hsa-miR-4656, hsa-miR-6806-5p, hsa-miR- 1233-5p, hsa-miR-328-5p, hsa-miR-4674, hsa- miR-2110, hsa-miR-6076, hsa-miR-3619-3p, hs a-miR-92a-2-5p, hsa-miR-128-1-5p, hsa-miR- 638, hsa-miR-2861, hsa-miR-371a-5p, hsa-miR -211-3p, hsa-miR-1273g-3p, hsa-miR-1203, hs a-miR-122-5p, hsa-miR-4258, hsa-miR-4484, h sa-miR-4648 or hsa-miR-6780b-5p, or a combination thereof the existence of a combination thereof, or a homologue thereof, a transcription product thereof, a variant thereof or a derivative thereof, The present invention allows the qualitative and / or quantitative measurement of the presence, expression level or abundance of a gene.

[0398] The target nucleic acid is a nucleic acid that is expressed by a nucleic acid sequence of a subject suffering from biliary tract cancer compared to a healthy subject. Depending on the type of gene, the expression levels of some genes may increase or decrease (see below). (These are referred to as "increase / decrease"). Therefore, the nucleic acid of the present invention can be used to detect the presence of biliary tract cancer in a patient suspected of having the disease. The expression level of the target nucleic acid is measured in body fluids derived from a subject (e.g., a human) and body fluids derived from a healthy subject. These can be used effectively to detect biliary tract cancer by comparing the results. The nucleic acid of the present invention is a nucleic acid obtained by analyzing a body fluid derived from a subject (e.g., a human) suspected of having biliary tract cancer and a colon cancer. For body fluids from cancer patients, stomach cancer patients, esophageal cancer patients, liver cancer patients, and patients with benign pancreatic and biliary diseases The expression levels of the target nucleic acids are measured and compared with those of other cancers and benign diseases. It can be effectively used to specifically detect biliary tract cancer.

[0399] Nucleic acid probes or primers that can be used in the present invention are those represented by SEQ ID NOs: 1 to 125 (preferably A base sequence represented by at least one of SEQ ID NOs: 1, 2, 4 to 125, and 466 to 478 or a nucleic acid probe capable of specifically binding to a polynucleotide consisting of SEQ ID NOs: 1 to 12. 5, amplifying a polynucleotide consisting of at least one of the nucleotide sequences represented by 466 to 478 This is a primer for broadening the scope.

[0400] Nucleic acid probes or primers that can be used in the present invention further include those of SEQ ID NOs: 126 to 148. A nucleic acid capable of specifically binding to a polynucleotide consisting of at least one of the base sequences represented by A probe or a probe consisting of at least one of the base sequences represented by SEQ ID NOs: 126 to 148 Primers for amplifying the polynucleotide may be included.

[0401] Specifically, the nucleic acid probe or primer is any one of SEQ ID NOs: 1 to 509. or a polynucleotide containing a base sequence in which u is t in the base sequence. A group of nucleotides and their complementary polynucleotides, a base sequence complementary to the base sequence Polynucleotides that hybridize with the DNA of interest under stringent conditions (see below) Otides and their complementary polynucleotides, and the bases of those polynucleotides A group of polynucleotides containing 15 or more, preferably 17 or more consecutive bases in the sequence These polynucleotides include a combination of one or more polynucleotides selected from the following: The method comprises the steps of: preparing a nucleic acid probe and a primer for detecting the above-mentioned biliary tract cancer marker, which is a target nucleic acid; It can be used as a

[0402] More specifically, examples of nucleic acid probes or primers that can be used in the present invention include the following: One or more polynucleotides selected from the group consisting of polynucleotides (a) to (e). is. (a) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide consisting of the base sequence in which u is replaced by t, a variant thereof, or a fragment thereof containing 15 or more consecutive bases, (b) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478; cleotide, (c) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding A polynucleotide consisting of a base sequence complementary to the base sequence in which u is t. a fragment thereof containing 15 or more consecutive bases, (d) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide comprising a base sequence complementary to the base sequence in which u is t ,and, (e) A polynucleotide that binds to any one of the polynucleotides (a) to (d) under stringent conditions. Hybridizing polynucleotide.

[0403] The nucleic acid probe or primer that can be used in the present invention further includes the above-mentioned polynucleotide ( In addition to at least one polynucleotide selected from the group consisting of a) to (e), A polynucleotide selected from the group consisting of the polynucleotides (f) to (j) below: It can contain (f) a base sequence represented by any one of SEQ ID NOs: 126 to 148 or the base sequence a polynucleotide consisting of a base sequence in which u is t, a variant thereof, a derivative thereof, or a fragment thereof containing 5 or more consecutive bases; (g) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 126 to 148; (h) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide consisting of a base sequence complementary to the base sequence in which u is t, and a variant thereof a fragment thereof containing 15 or more consecutive bases, (i) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide comprising a base sequence complementary to the base sequence in which u is t; and (j) A method for detecting a polynucleotide that is hybridized with any one of the polynucleotides (f) to (i) under stringent conditions. Hybridizing polynucleotide.

[0404] In the above polynucleotide, "a fragment containing 15 or more consecutive bases" means each polynucleotide. In a base sequence of a polynucleotide, for example, 15 consecutive bases or less than the total number of bases in the sequence, It may contain a range of base numbers, such as 7 to less than the total number of bases in the sequence, or 19 to less than the total number of bases in the sequence. The present invention can be implemented in the following ways, but is not limited to these.

[0405] The polynucleotides or fragments thereof used in the present invention may be DNA. RNA may also be used.

[0406] The above polynucleotides that can be used in the present invention can be synthesized by DNA recombination techniques, PCR methods, DNA / It can be prepared using common techniques such as methods using an automatic RNA synthesizer.

[0407] DNA recombination techniques and PCR methods are described, for example, in Ausubel et al., Current Proc. otocols in Molecular Biology, John Wille y & Sons, US (1993); Sambrook et al., Molecula r Cloning A Laboratory Manual, Cold Spr. Harbor Laboratory Press, US (1989), etc. The techniques described in can be used.

[0408] Human-derived hsa-miR-125 represented by SEQ ID NOs: 1 to 148 and 466 to 478 a-3p, hsa-miR-6893-5p, hsa-miR-204-3p, hsa- miR-4476, hsa-miR-4294, hsa-miR-150-3p, hsa -miR-6729-5p, hsa-miR-7641, hsa-miR-6765-3 p, hsa-miR-6820-5p, hsa-miR-575, hsa-miR-68 36-3p, hsa-miR-1469, hsa-miR-663a, hsa-miR- 6075, hsa-miR-4634, hsa-miR-423-5p, hsa-miR -4454, hsa-miR-7109-5p, hsa-miR-6789-5p, hs a-miR-6877-5p, hsa-miR-4792, hsa-miR-4530, hsa-miR-7975, hsa-miR-6724-5p, hsa-miR-807 3, hsa-miR-7977, hsa-miR-1231, hsa-miR-6799 -5p, hsa-miR-615-5p, hsa-miR-4450, hsa-miR- 6726-5p、hsa-miR-6875-5p、hsa-miR-4734、hsa -miR-16-5p、hsa-miR-602、hsa-miR-4651、hsa- miR-8069, hsa-miR-1238-5p, hsa-miR-6880-5p hsa-miR-8072, hsa-miR-4723-5p, hsa-miR-47 32-5p、hsa-miR-6125、hsa-miR-6090、hsa-miR- 7114-5p、hsa-miR-564、hsa-miR-451a、hsa-miR -3135b、hsa-miR-4497、hsa-miR-4665-5p、hsa- miR-3622a-5p、hsa-miR-6850-5p、hsa-miR-682 1-5p、hsa-miR-5100、hsa-miR-6872-3p、hsa-mi R-4433-3p、hsa-miR-1227-5p、hsa-miR-3188、h sa-miR-7704、hsa-miR-3185、hsa-miR-1908-3p hsa-miR-6781-5p, hsa-miR-6805-5p, hsa-miR -8089、hsa-miR-665、hsa-miR-4486、hsa-miR-6 722-3p、hsa-miR-1260a、hsa-miR-4707-5p、hsa -miR-6741-5p、hsa-miR-1260b、hsa-miR-1246、 hsa-miR-6845-5p、hsa-miR-4638-5p、hsa-miR- 6085、hsa-miR-1228-3p、hsa-miR-4534、hsa-mi R-5585-3p、hsa-miR-4741、hsa-miR-4433b-3p、 hsa-miR-197-5p、hsa-miR-718、hsa-miR-4513、 hsa-miR-4446-3p、hsa-miR-619-5p、hsa-miR-6 816-5p、hsa-miR-6778-5p、hsa-miR-24-3p、hsa -miR-1915-3p、hsa-miR-4665-3p、hsa-miR-444 9、hsa-miR-6889-5p、hsa-miR-486-3p、hsa-miR -7113-3p、hsa-miR-642a-3p、hsa-miR-7847-3p hsa-miR-6768-5p, hsa-miR-1290, hsa-miR-71 08-5p、hsa-miR-92b-5p、hsa-miR-663b、hsa-mi R-3940-5p、hsa-miR-4467、hsa-miR-6858-5p、h sa-miR-4417、hsa-miR-3665、hsa-miR-4736、hs a-miR-4687-3p、hsa-miR-1908-5p、hsa-miR-51 95-3p、hsa-miR-4286、hsa-miR-3679-3p、hsa-m iR-6791-5p、hsa-miR-1202、hsa-miR-3656、hsa -miR-4746-3p、hsa-miR-3184-5p、hsa-miR-393 7, hsa-miR-6515-3p, hsa-miR-6132, hsa-miR-1 87-5p、hsa-miR-7111-5p、hsa-miR-5787、hsa-m iR-6779-5p、hsa-miR-6808-5p、hsa-miR-6774- 5p、hsa-miR-4656、hsa-miR-6806-5p、hsa-miR- 1233-5p、hsa-miR-328-5p、hsa-miR-4674、hsa- miR-2110, hsa-miR-6076, hsa-miR-3619-3p, hs a-miR-92a-2-5p, hsa-miR-128-1-5p, hsa-miR- 638, hsa-miR-2861, hsa-miR-371a-5p, hsa-miR -211-3p, hsa-miR-1273g-3p, hsa-miR-1203, hs a-miR-122-5p, hsa-miR-4258, hsa-miR-4484, h sa-miR-4648 and hsa-miR-6780b-5p are known and, as described above, Therefore, by cloning this gene, to prepare polynucleotides as nucleic acid probes or primers that can be used in the present invention. It is possible.

[0409] Such nucleic acid probes or primers can be chemically synthesized using an automated DNA synthesizer. This synthesis is generally carried out using the phosphoramidite method, which The automated DNA synthesizer can automatically synthesize single-stranded DNA up to about 100 bases. For example, Polygen, ABI, Applied BioSystems, etc. It is commercially available.

[0410] Alternatively, the polynucleotides of the present invention can be produced by cDNA cloning techniques. cDNA cloning technology is also possible, for example, microRNA cloning You can use Kit Wako etc.

[0411] Here, the base sequence is represented by any one of SEQ ID NOs: 1 to 148, 466 to 478. The sequences of the nucleic acid probes and primers for detecting the polynucleotides are does not exist in vivo as its precursor. For example, SEQ ID NO: 51 and SEQ ID NO: 91 The base sequence represented by is generated from a precursor represented by SEQ ID NO: 201, has a hairpin-like structure as shown in FIG. 1 and is represented by SEQ ID NO: 51 and SEQ ID NO: 91. The base sequences of SEQ ID NO: 51 and SEQ ID NO: 52 have mismatch sequences. The completely complementary base sequence to the base sequence represented by No. 91 is naturally produced in vivo. Similarly, the bases represented by any of SEQ ID NOs: 1 to 148, 466 to 478 The nucleic acid probes and primers used to detect the sequences are artificial base sequences that do not exist in vivo. It will have columns.

[0412] 3. Biliary tract cancer detection kit or device The present invention also relates to a method for measuring a target nucleic acid that is a biliary tract cancer marker, comprising the steps of: Polynucleotides that can be used as nucleic acid probes or primers (including mutants, fragments, or a derivative thereof (hereinafter sometimes referred to as a detection polynucleotide). or a kit or device for detecting biliary tract cancer comprising a plurality of the above components.

[0413] The target nucleic acid that is a biliary tract cancer marker in the present invention is preferably selected from the following Group 1: To be: miR-125a-3p, miR-6893-5p, miR-204-3p, miR- 4476, miR-4294, miR-150-3p, miR-6729-5p, miR -7641, miR-6765-3p, miR-6820-5p, miR-575, mi R-6836-3p, miR-1469, miR-663a, miR-6075, miR -4634, miR-423-5p, miR-4454, miR-7109-5p, mi R-6789-5p、miR-6877-5p、miR-4792、miR-4530、 miR-7975, miR-6724-5p, miR-8073, miR-7977, m iR-1231、miR-6799-5p、miR-615-5p、miR-4450、 miR-6726-5p、miR-6875-5p、miR-4734、miR-16- 5p、miR-602、miR-4651、miR-8069、miR-1238-5p miR-6880-5p, miR-8072, miR-4723-5p, miR-47 32-5p、miR-6125、miR-6090、miR-7114-5p、miR- 564, miR-451a, miR-3135b, miR-4497, miR-4665 -5p、miR-3622a-5p、miR-6850-5p、miR-6821-5p miR-5100, miR-6872-3p, miR-4433-3p, miR-12 27-5p、miR-3188、miR-7704、miR-3185、miR-190 8-3p、miR-6781-5p、miR-6805-5p、miR-8089、mi R-665、miR-4486、miR-6722-3p、miR-1260a、miR -4707-5p、miR-6741-5p、miR-1260b、miR-1246、 miR-6845-5p, miR-4638-5p, miR-6085, miR-122 8-3p、miR-4534、miR-5585-3p、miR-4741、miR-4 433b-3p、miR-197-5p、miR-718、miR-4513、miR- 4446-3p、miR-619-5p、miR-6816-5p、miR-6778- 5p, miR-24-3p, miR-1915-3p, miR-4665-3p, miR -4449, miR-6889-5p, miR-486-3p, miR-7113-3p , miR-642a-3p, miR-7847-3p, miR-6768-5p, miR -1290, miR-7108-5p, miR-92b-5p, miR-663b, mi R-3940-5p, miR-4467, miR-6858-5p, miR-4417, miR-3665, miR-4736, miR-4687-3p, miR-1908-5 p, miR-5195-3p, miR-4286, miR-3679-3p, miR-6 791-5p, miR-1202, miR-3656, miR-4746-3p, miR -3184-5p, miR-3937, miR-6515-3p, miR-6132, m iR-187-5p, miR-7111-5p, miR-5787, miR-6779- 5p, miR-4516, miR-4649-5p, miR-760, miR-3162 -5p, miR-3178, miR-940, miR-4271, miR-6769b- 5p, miR-4508, miR-6826-5p, miR-6757-5p, miR- 3131 and miR-1343-3p.

[0414] The additional target nucleic acid that may be used for measurement is preferably selected from the following group 2: : miR-6808-5p, miR-6774-5p, miR-4656, miR-6 806-5p, miR-1233-5p, miR-328-5p, miR-4674, m iR-2110, miR-6076, miR-3619-3p, miR-92a-2-5 p, miR-128-1-5p, miR-638, miR-2861, miR-371a -5p, miR-211-3p, miR-1273g-3p, miR-1203, miR -122-5p, miR-4258, miR-4484, miR-4648 and miR- 6780b-5p.

[0415] The kit or device of the present invention specifically binds to the target nucleic acid that is the biliary tract cancer marker. A nucleic acid capable of synthesizing, preferably, the nucleic acid probe or primer described in 2 above, specifically, One or more polynucleotides selected from the polynucleotides described in item 2 or This includes mutants of the above.

[0416] Specifically, the kit or device of the present invention includes SEQ ID NOs: 1 to 125 and 466 to 478. or a base sequence in which u is t in the base sequence, a polynucleotide comprising (or consisting of) the complementary sequence thereof; Polynucleotides that hybridize with those polynucleotides under stringent conditions A hybridizing polynucleotide or 15 or more consecutive sequences of such polynucleotide sequences The nucleic acid sequence may include at least one or more mutants or fragments containing the same base.

[0417] The kit or device of the present invention further comprises a compound represented by any one of SEQ ID NOs: 126 to 148. A base sequence, or a base sequence in which u is t in the base sequence (or a polynucleotide comprising (or consisting of) its complementary sequence; Polynucleotides that hybridize under stringent conditions with these polynucleotides. nucleotides or variants containing 15 or more consecutive bases of their polynucleotide sequences or fragments thereof.

[0418] The fragments that can be contained in the kit or device of the present invention include, for example, the following (1) to (2): The polynucleotide is one or more, preferably two or more, selected from the group consisting of: (1) In the base sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, u is A polynucleotide containing 15 or more consecutive bases in the base sequence t or its complementary sequence Reotide. (2) A base in which u is t in the base sequence represented by any one of SEQ ID NOs: 126 to 148 A polynucleotide containing 15 or more consecutive bases in a sequence or its complementary sequence.

[0419] In a preferred embodiment, the polynucleotide is selected from the group consisting of SEQ ID NOs: 1 to 125, 466 to 47 A base sequence represented by any one of 8, or a base sequence in which u is t a polynucleotide consisting of the complementary sequence thereof; A polynucleotide that hybridizes under stringent conditions with a nucleotide, or A mutation containing 15 or more, preferably 17 or more, more preferably 19 or more consecutive bases. It is a different body.

[0420] In a preferred embodiment, the polynucleotide is any one of SEQ ID NOs: 126 to 148. A base sequence represented by either of the above, or a base sequence in which u is t in the base sequence, a polynucleotide comprising the sequence thereof, a polynucleotide comprising the sequence thereof, Polynucleotides that hybridize under stringent conditions with the nucleotides, or their A mutant containing 15 or more, preferably 17 or more, more preferably 19 or more consecutive bases. be.

[0421] In a preferred embodiment, the fragments are 15 or more, preferably 17 or more, more preferably It can be a polynucleotide containing 19 or more consecutive bases.

[0422] In the present invention, the size of a polynucleotide fragment is determined based on the base sequence of each polynucleotide. For example, from 15 to less than the total number of bases in the sequence, from 17 to less than the total number of bases in the sequence , the number of bases may range from 19 to less than the total number of bases in the sequence.

[0423] The combination of the above polynucleotides constituting the kit or device of the present invention may be Specifically, the sequence numbers shown in Table 1 below (the sequence numbers corresponding to the miRNA markers in Table 1) , SEQ ID NOs: 1 to 148 and 466 to 478) or a complementary sequence thereof Examples of the polynucleotides include any combination of the above polynucleotides consisting of These are merely examples, and all other possible combinations are encompassed by the present invention. Let's say.

[0424] For example, in the present invention, a kit or device for distinguishing between biliary tract cancer and healthy subjects is constructed. The above combinations include those consisting of the base sequences shown in the sequence numbers in Table 1. It is desirable to combine two or more of the above polynucleotides, and usually two combinations are used. This allows for sufficient performance.

[0425] Specifically, it consists of a base sequence for distinguishing between biliary tract cancer and healthy subjects or its complementary sequence. Two combinations of polynucleotides are shown in SEQ ID NOs: 1 to 148 and 466 to 478. A combination of two polynucleotides selected from the above polynucleotides consisting of the base sequences represented by That is, the newly discovered base sequences represented by SEQ ID NOs: 1 to 125 and 466 to 478 A combination containing at least one polynucleotide having the above structure is preferred.

[0426] In addition, we have developed cancer-specific polymerases that can distinguish biliary tract cancer from not only healthy subjects but also other cancers. As a combination of nucleotides, for example, SEQ ID NOs: 1, 4, 5, 11, 12, 15, 2 3, 29, 39, 40, 54, 76, 79, 91, 103, 115, 121, 134, 1 43, 466, 469, 472, 473, and 474 or the nucleotide sequences thereof A group consisting of polynucleotides with complementary sequences (hereinafter, this group is referred to as "cancer type-specific polynucleotides"). At least one polynucleotide selected from the "nucleotide group 1" and other sequences Multiple combinations of the sequence numbers with the polynucleotides are preferred.

[0427] Furthermore, we have developed cancer-specific polymerases that can distinguish biliary tract cancer from not only healthy subjects but also other cancers. The combination of nucleotides is a polynucleotide selected from Cancer Type-Specific Polynucleotide Group 1. A combination of several polynucleotides is more preferred.

[0428] Furthermore, we have developed cancer-specific polymerases that can distinguish biliary tract cancer from not only healthy subjects but also other cancers. The combination of nucleotides is a polynucleotide selected from Cancer Type-Specific Polynucleotide Group 1. Among the combinations of several polynucleotides, those included in Cancer Type-Specific Polynucleotide Group 1 The base sequences represented by SEQ ID NOs: 4, 5, 12, 15 and 40 or their complementary sequences A group consisting of polynucleotides consisting of (hereinafter, this group is referred to as "cancer type-specific polynucleotides") A combination containing at least one polynucleotide selected from the group consisting of More preferable.

[0429] The number of combinations of the above cancer type-specific polynucleotides is 1, 2, or , 3, 4, 5, 6, 7, 8, 9, 10 or more combinations However, more preferably, a combination of four or more is possible, and usually, a combination of four is possible. This allows for sufficient performance.

[0430] The following are non-limiting examples of sequences consisting of the base sequence represented by SEQ ID NO: 4 or its complementary sequence: Polynucleotide and three polynucleotides selected from cancer type-specific polynucleotide group 1 A polynucleotide consisting of a base sequence represented by the SEQ ID NO of the nucleotide or its complementary sequence. Examples of combinations with are shown below.

[0431] (1) SEQ ID NOs: 4, 15, 54, 115 (markers: miR-4476, miR-607) 5, miR-6821-5p, miR-1202) combination (2) SEQ ID NOs: 4, 5, 12, 76 (markers: miR-4476, miR-4294, miR-6836-3p, miR-6085) (3) SEQ ID NOs: 4, 5, 12, 115 (markers: miR-4476, miR-4294) , miR-6836-3p, miR-1202) combination (4) SEQ ID NOs: 4, 12, 15, 474 (markers: miR-4476, miR-683 6-3p, miR-6075, miR-4508) (5) SEQ ID NOs: 4, 15, 29, 115 (markers: miR-4476, miR-607) 5, miR-6799-5p, miR-1202) combination

[0432] The following is a non-limiting example of a sequence consisting of the base sequence represented by SEQ ID NO: 5 or its complementary sequence: Polynucleotide and three polynucleotides selected from cancer type-specific polynucleotide group 1 A polynucleotide consisting of a base sequence represented by the SEQ ID NO of the nucleotide or its complementary sequence. Examples of combinations with are shown below.

[0433] (1) SEQ ID NOs: 5, 76, 12, 115 (marker: hsa-miR-4294, hsa -miR-6085, hsa-miR-6836-3p, hsa-miR-1202) combination (2) SEQ ID NOs: 5, 76, 54, 115 (marker: hsa-miR-4294, hsa -miR-6085, hsa-miR-6821-5p, hsa-miR-1202) combination (3) SEQ ID NOs: 5, 23, 12, 115 (marker: hsa-miR-4294, hsa -miR-4530, hsa-miR-6836-3p, hsa-miR-1202) combination (4) SEQ ID NOs: 5, 12, 115, 91 (marker: hsa-miR-4294, hsa -miR-6836-3p, hsa-miR-1202, hsa-miR-4665-3 p) combination (5) SEQ ID NOs: 5, 1, 23, 4 (markers: hsa-miR-4294, hsa-mi R-125a-3p, hsa-miR-4530, hsa-miR-4476) Match

[0434] The following are non-limiting examples of sequences consisting of the base sequence represented by SEQ ID NO: 12 or its complementary sequence: and three polynucleotides selected from cancer type-specific polynucleotide group 1. A polynucleotide consisting of a base sequence represented by the sequence number of the nucleic acid fragment or a complementary sequence thereof. Examples of combinations with the code are shown below.

[0435] (1) SEQ ID NOs: 5, 12, 29, 115 (markers: miR-4294, miR-683) 6-3p, miR-6799-5p, miR-1202) (2) SEQ ID NOs: 12, 15, 23, 115 (marker: miR-6836-3p, miR -6075, miR-4530, miR-1202) (3) SEQ ID NOs: 5, 12, 115, 469 (markers: miR-4294, miR-68 36-3p, miR-3162-5p, miR-1202) (4) SEQ ID NOs: 5, 12, 115, 472 (markers: miR-4294, miR-68 36-3p, miR-1202, miR-4271) (5) SEQ ID NOs: 5, 12, 76, 115 (markers: miR-4294, miR-608) 5, miR-1202, miR-6836-3p) combination

[0436] The following are non-limiting examples of sequences consisting of the base sequence represented by SEQ ID NO: 15 or its complementary sequence: and three polynucleotides selected from cancer type-specific polynucleotide group 1. A polynucleotide consisting of a base sequence represented by the sequence number of the nucleic acid fragment or a complementary sequence thereof. Examples of combinations with the code are shown below.

[0437] (1) SEQ ID NOs: 15, 29, 1, 12 (markers: hsa-miR-6075, hsa- miR-6799-5p, hsa-miR-125a-3p, hsa-miR-6836 -3p) combination (2) SEQ ID NOs: 15, 12, 11, 143 (markers: hsa-miR-6075, hs a-miR-6836-3p, hsa-miR-575, hsa-miR-1203) combination (3) SEQ ID NOs: 15, 76, 121, 39 (markers: hsa-miR-6075, hs a-miR-6085, hsa-miR-6132, hsa-miR-1238-5p) Combination of (4) SEQ ID NOs: 15, 76, 54, 121 (markers: hsa-miR-6075, hs a-miR-6085, hsa-miR-6821-5p, hsa-miR-6132) Combination of (5) SEQ ID NOs: 15, 40, 1, 23 (markers: hsa-miR-6075, hsa- miR-6880-5p, hsa-miR-125a-3p, hsa-miR-4530 ) combination

[0438] The following are non-limiting examples of sequences consisting of the base sequence represented by SEQ ID NO: 40 or its complementary sequence: and three polynucleotides selected from cancer type-specific polynucleotide group 1. A polynucleotide consisting of a base sequence represented by the sequence number of the nucleic acid fragment or a complementary sequence thereof. Examples of combinations with the code are shown below.

[0439] (1) SEQ ID NOs: 12, 40, 472, 473 (markers: miR-6836-3p, mi miR-6880-5p, miR-4271, miR-6769b-5p) (2) SEQ ID NOs: 12, 23, 40, 466 (marker: miR-6836-3p, miR -4530, miR-6880-5p, miR-4516) (3) SEQ ID NOs: 12, 23, 40, 134 (marker: miR-6836-3p, miR -4530, miR-6880-5p, miR-6076) (4) SEQ ID NOs: 15, 40, 121, 134 (markers: miR-6075, miR-6 880-5p, miR-6132, miR-6076) (5) SEQ ID NOs: 15, 40, 54, 76 (markers: miR-6075, miR-688) 0-5p, miR-6821-5p, miR-6085)

[0440] The kit or device of the present invention may contain the polynucleotide of the present invention described above ( This may include mutants, fragments, or derivatives. It may include known polynucleotides or polynucleotides that may be discovered in the future. Cut.

[0441] The kit of the present invention may contain, in addition to the polynucleotide of the present invention described above, CEA , CA19-9, SPan-1, DUPAN-2, CA50, CA195, IL-6, C Known markers for biliary tract cancer testing, such as A242, TAG-72, urinary fucose, POA, and TPS Antibodies for measuring the marker can also be included.

[0442] The above polynucleotides contained in the kit of the present invention may be used individually or in any combination. It can be packaged in a container.

[0443] The kit of the present invention includes a nucleic acid extractor for extracting nucleic acid (e.g., total RNA) from body fluids, cells, or tissues. kit for extracting the nucleic acid, fluorescent labeling material, nucleic acid amplification enzyme and culture medium, instruction manual, etc. It can be done.

[0444] The device of the present invention is a device in which nucleic acids such as the polynucleotides of the present invention described above are For example, a device for measuring a cancer marker bound or attached to a solid phase. Examples of materials include plastic, paper, glass, and silicon, which are preferred due to their ease of processing. The preferred material of the solid phase is plastic. The shape of the solid phase is arbitrary, for example, square, round, The device of the present invention may be in the form of a strip, a film, or the like. This includes devices for measurements by DNA technology, specifically blotting devices, nucleic acid Examples include arrays (such as microarrays, DNA chips, and RNA chips).

[0445] Nucleic acid array technology can be used to add functional groups such as L-lysine coating, amino groups, and carboxyl groups as needed. A spotter or arrayer is placed on the surface of a solid phase that has been subjected to surface treatment such as functional group introduction. A method of spotting nucleic acids using a high-density dispenser, in which minute droplets are dispensed from a nozzle onto a piezoelectric element, etc. A method of spraying nucleic acids onto a solid phase using an inkjet that sprays nucleic acids from a nozzle, The nucleic acids can be linked or attached one by one using methods such as nucleotide synthesis. By using this, an array such as a chip is produced, and hybridization is performed using this array. This is a technology for measuring target nucleic acids using

[0446] The kit or device of the present invention is a method for detecting a small amount of miRNA, which is a biliary tract cancer marker of Group 1. At least one, preferably at least two, more preferably at least three and most preferably at least five or more polynucleotides specific to each of the polynucleotides. The kit or device of the present invention further optionally comprises a nucleic acid capable of binding to the above group. At least one of the miRNAs listed in Table 2, which are biliary tract cancer markers, is selected, preferably at least two. More preferably, at least three or more polynucleotides, and most preferably all five polynucleotides. The nucleic acid sequence can include nucleic acids capable of specifically binding to each of the peptides.

[0447] The kit or device of the present invention can be used to detect the following four types of biliary tract cancer. do.

[0448] 4. Methods for detecting biliary tract cancer The present invention further relates to the kit or device of the present invention (usable in the present invention) described in 3. above. The following groups: miR-125a-3p, miR-125b, miR-125c, miR-125d, miR-125e, miR-125f, miR-125g, miR-125h, miR-125i, miR-125j ...i, miR-125j, miR-125p, miR-125i, R-6893-5p, miR-204-3p, miR-4476, miR-4294, m iR-150-3p, miR-6729-5p, miR-7641, miR-6765- 3p, miR-6820-5p, miR-575, miR-6836-3p, miR-1 469, miR-663a, miR-6075, miR-4634, miR-423-5 p, miR-4454, miR-7109-5p, miR-6789-5p, miR-6 877-5p, miR-4792, miR-4530, miR-7975, miR-67 24-5p, miR-8073, miR-7977, miR-1231, miR-679 9-5p, miR-615-5p, miR-4450, miR-6726-5p, miR -6875-5p, miR-4734, miR-16-5p, miR-602, miR- 4651, miR-8069, miR-1238-5p, miR-6880-5p, mi R-8072, miR-4723-5p, miR-4732-5p, miR-6125, miR-6090, miR-7114-5p, miR-564, miR-451a, mi R-3135b, miR-4497, miR-4665-5p, miR-3622a-5 p, miR-6850-5p, miR-6821-5p, miR-5100, miR-6 872-3p, miR-4433-3p, miR-1227-5p, miR-3188, miR-7704, miR-3185, miR-1908-3p, miR-6781-5 p, miR-6805-5p, miR-8089, miR-665, miR-4486, miR-6722-3p, miR-1260a, miR-4707-5p, miR-67 41-5p, miR-1260b, miR-1246, miR-6845-5p, miR -4638-5p, miR-6085, miR-1228-3p, miR-4534, m iR-5585-3p, miR-4741, miR-4433b-3p, miR-197 -5p, miR-718, miR-4513, miR-4446-3p, miR-619 -5p, miR-6816-5p, miR-6778-5p, miR-24-3p, mi R-1915-3p, miR-4665-3p, miR-4449, miR-6889- 5p, miR-486-3p, miR-7113-3p, miR-642a-3p, mi R-7847-3p, miR-6768-5p, miR-1290, miR-7108- 5p, miR-92b-5p, miR-663b, miR-3940-5p, miR-4 467, miR-6858-5p, miR-4417, miR-3665, miR-47 36, miR-4687-3p, miR-1908-5p, miR-5195-3p, m iR-4286, miR-3679-3p, miR-6791-5p, miR-1202 , miR-3656, miR-4746-3p, miR-3184-5p, miR-39 37, miR-6515-3p, miR-6132, miR-187-5p, miR-7 111-5p, miR-5787, and miR-6779-5p selected from cholangiocarcinoma The expression levels of genes from the following groups, as well as, optionally, miR-6808-5p, miR- 6774-5p, miR-4656, miR-6806-5p, miR-1233-5p , miR-328-5p, miR-4674, miR-2110, miR-6076, m iR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR -638, miR-2861, miR-371a-5p, miR-211-3p, miR -1273g-3p, miR-1203, miR-122-5p, miR-4258, m iR-4484, miR-4648, miR-6780b-5p, miR-4516, m iR-4649-5p, miR-760, miR-3162-5p, miR-3178, miR-940, miR-4271, miR-6769b-5p, miR-4508, m iR-6826-5p, miR-6757-5p, miR-3131, and miR-1 343-3p, and the expression level of a gene derived from biliary tract cancer, The expression level of cancer-derived genes was measured in vitro, and furthermore, the level of cancer-derived genes was measured in patients suspected of having biliary tract cancer. Blood, serum, plasma, etc. collected from subjects and healthy subjects (including non-biliary tract cancer patients) For a sample, the expression level of the gene in the sample and the control expression level of a healthy subject are used to, for example, When both expression levels are compared and there is a statistically significant difference in the expression level of the target nucleic acid in the sample, A method for detecting biliary tract cancer is provided, comprising assessing a subject as having biliary tract cancer. do.

[0449] The method of the present invention enables early cancer diagnosis with high sensitivity and specificity in a minimally invasive manner. This will lead to earlier treatment and improved prognosis, and also facilitate monitoring of disease progression and external This allows for the monitoring of the effectiveness of medical, radiotherapeutic, and chemotherapeutic treatments.

[0450] In the method of the present invention for extracting genes derived from biliary tract cancer from specimens such as blood, serum, and plasma, three steps are performed: D-Gene® RNA extraction reagent from Add the RNA extraction reagent in the liquid sample kit (Toray Industries, Inc.) It is particularly preferred to prepare it by the general acid phenol method (Acid Guanidin The ammonium-phenol-chloroform (AGPC) method may be used, or izol (registered trademark) (Life Technologies) may be used. izol (Life Technologies) and Isogen (Nippon Gene) It may also be prepared by adding an RNA extraction reagent containing acidic phenol such as mi Kits such as the RNeasy® Mini Kit (Qiagen) are available. However, the method is not limited to these.

[0451] The present invention also relates to a method for detecting biliary tract cancer in a specimen from a subject using the kit or device of the present invention. The present invention provides a use for detecting the expression products of miRNA genes in vitro.

[0452] In the above-mentioned method of the present invention, the above-mentioned kit or device comprises the above-mentioned Polynucleotides usable in the Used.

[0453] In the detection or (genetic) diagnosis of biliary tract cancer of the present invention, The polynucleotides contained therein can be used as probes or primers. When using TaqMan ( Registered trademark) MicroRNA Assays, Qiagen's miScript P CR System, etc. can be used, but the method is not limited to these.

[0454] The polynucleotides contained in the kit or device of the present invention can be analyzed by Northern blotting, Northern blot, in situ hybridization, Northern hybridization Hybridization techniques such as ionization and Southern hybridization, and quantification By using known methods to specifically detect specific genes, such as quantitative amplification techniques such as RT-PCR. In the above cases, it can be used as a primer or probe according to standard methods. Depending on the type of detection method used, the body fluids may include blood, serum, plasma, urine, etc. Alternatively, total RNA prepared by the above method from such a body fluid is collected. Furthermore, various polymerase chains including cDNA prepared from the RNA may be used. Oligonucleotides may also be used.

[0455] The kit or device of the present invention is useful for diagnosing biliary tract cancer or detecting the presence or absence of the disease. Specifically, the detection of biliary tract cancer using the kit or device is The kit or device is used to test blood, serum, plasma, urine, or other samples from subjects suspected of having the disease. The expression level of the gene detected by the nucleic acid probe or primer contained in the This can be done by detecting the blood of a subject suspected of having biliary tract cancer. At least one of SEQ ID NOs: 1 to 125, 466 to 478 in a sample such as serum, plasma, or urine The base sequence shown above or its complementary sequence, and optionally SEQ ID NOs: 126 to 127 A polynucleotide consisting of one or more of the base sequences represented by 48 or their complementary sequences. Target miRNA marker measured by (including variants, fragments or derivatives thereof) The expression levels of the proteins were compared with those in blood, serum, plasma, urine, and other samples from healthy individuals. If there is a statistically significant difference, the subject can be assessed as having biliary tract cancer. Cut.

[0456] The method of the present invention can be performed using abdominal ultrasound, CT scan, endoscopic retrograde cholangiopancreatography, The method of the present invention can be combined with an imaging diagnostic method such as endoscopic ultrasound. It is possible to specifically detect cancer and to substantially distinguish it from cancers other than biliary tract cancer. In particular, in the case of pancreatic cancer, there are some miRNA markers in common with those in the case of biliary tract cancer. However, depending on how the discriminant boundary is determined by the discriminant, This may allow the differentiation of pancreatic cancer from other cancers, or may be achieved by using imaging diagnostic methods such as those mentioned above. These cancers can be identified by combining this with other diagnostic methods.

[0457] The expression product of a gene derived from biliary tract cancer is not contained in a sample obtained using the kit or device of the present invention. The method for detecting whether the gene expression product derived from biliary tract cancer is not rare or contains the gene expression product derived from biliary tract cancer is The expression level of the target gene contained in the collected body fluids such as blood, serum, plasma, and urine is measured. , one or more polynucleotides selected from the group of polynucleotides of the present invention (mutants, The presence or absence of biliary tract cancer is evaluated by measuring the amount of biliary tract cancer-causing agent (including its fragments and derivatives). Furthermore, the method for detecting biliary tract cancer of the present invention can be used to detect, for example, biliary tract cancer. In patients with biliary tract cancer, the effect of administering a therapeutic drug to improve the disease The presence or absence of improvement or the degree of improvement can also be evaluated or diagnosed.

[0458] The method of the present invention includes, for example, the following steps (a), (b) and (c): (a) A sample from a subject is subjected to in vitro analysis using a polynucleotide in the kit or device of the present invention. contacting with a nucleotide; (b) measuring the expression level of the target nucleic acid in the sample by using the polynucleotide as a nucleic acid probe or primer; measuring using the (c) Based on the results of (b), evaluate the presence or absence of biliary tract cancer (cells) in the subject. a step of: may include:

[0459] Specifically, the present invention relates to miR-125a-3p, miR-6893-5p, miR- 204-3p, miR-4476, miR-4294, miR-150-3p, miR- 6729-5p, miR-7641, miR-6765-3p, miR-6820-5p , miR-575, miR-6836-3p, miR-1469, miR-663a, m iR-6075, miR-4634, miR-423-5p, miR-4454, miR -7109-5p, miR-6789-5p, miR-6877-5p, miR-479 2, miR-4530, miR-7975, miR-6724-5p, miR-8073 , miR-7977, miR-1231, miR-6799-5p, miR-615-5 p, miR-4450, miR-6726-5p, miR-6875-5p, miR-4 734、miR-16-5p、miR-602、miR-4651、miR-8069、 miR-1238-5p, miR-6880-5p, miR-8072, miR-472 3-5p、miR-4732-5p、miR-6125、miR-6090、miR-7 114-5p、miR-564、miR-451a、miR-3135b、miR-44 97、miR-4665-5p、miR-3622a-5p、miR-6850-5p、 miR-6821-5p, miR-5100, miR-6872-3p, miR-443 3-3p、miR-1227-5p、miR-3188、miR-7704、miR-3 185、miR-1908-3p、miR-6781-5p、miR-6805-5p、 miR-8089, miR-665, miR-4486, miR-6722-3p, mi R-1260a、miR-4707-5p、miR-6741-5p、miR-1260 b、miR-1246、miR-6845-5p、miR-4638-5p、miR-6 085、miR-1228-3p、miR-4534、miR-5585-3p、miR -4741、miR-4433b-3p、miR-197-5p、miR-718、mi R-4513、miR-4446-3p、miR-619-5p、miR-6816-5 p、miR-6778-5p、miR-24-3p、miR-1915-3p、miR- 4665-3p、miR-4449、miR-6889-5p、miR-486-3p、 miR-7113-3p、miR-642a-3p、miR-7847-3p、miR- 6768-5p、miR-1290、miR-7108-5p、miR-92b-5p、 miR-663b, miR-3940-5p, miR-4467, miR-6858-5 p, miR-4417, miR-3665, miR-4736, miR-4687-3p , miR-1908-5p, miR-5195-3p, miR-4286, miR-36 79-3p, miR-6791-5p, miR-1202, miR-3656, miR- 4746-3p, miR-3184-5p, miR-3937, miR-6515-3p , miR-6132, miR-187-5p, miR-7111-5p, miR-578 7, miR-6779-5p, miR-4516, miR-4649-5p, miR-7 60, miR-3162-5p, miR-3178, miR-940, miR-4271 , miR-6769b-5p, miR-4508, miR-6826-5p, miR-6 757-5p, miR-3131, and miR-1343-3p. and specifically binds at least one or more, preferably at least two or more polynucleotides The expression level of the target nucleic acid in a specimen of a subject is measured using the nucleic acid capable of binding, and the measured The expression levels measured and the control expression levels measured in similarly healthy individuals were used to determine whether the subject had biliary tract cancer. This includes in vitro assessment of whether or not a patient has biliary tract cancer. and a method for detecting biliary tract cancer.

[0460] In this specification, "evaluation" refers to in vitro testing, not to a doctor's judgment. This is evaluation support based on the results of testing.

[0461] As described above, in a preferred embodiment of the method of the present invention, specifically, miR-12 5a-3p is hsa-miR-125a-3p, and miR-6893-5p is hsa -miR-6893-5p, and miR-204-3p is hsa-miR-204-3 p, miR-4476 is hsa-miR-4476, and miR-4294 is h sa-miR-4294 and miR-150-3p is hsa-miR-150-3p , miR-6729-5p is hsa-miR-6729-5p, and miR-7 641 is hsa-miR-7641, and miR-6765-3p is hsa-miR- 6765-3p, and miR-6820-5p is hsa-miR-6820-5p. miR-575 is hsa-miR-575, and miR-6836-3p is hsa -miR-6836-3p, and miR-1469 is hsa-miR-1469 , miR-663a is hsa-miR-663a, and miR-6075 is hsa-m iR-6075, miR-4634 is hsa-miR-4634, and miR- 423-5p is hsa-miR-423-5p, and miR-4454 is hsa-mi R-4454, and miR-7109-5p is hsa-miR-7109-5p , miR-6789-5p is hsa-miR-6789-5p, and miR-6877 -5p is hsa-miR-6877-5p, and miR-4792 is hsa-miR- 4792, miR-4530 is hsa-miR-4530, and miR-797 5 is hsa-miR-7975, and miR-6724-5p is hsa-miR-67 24-5p, miR-8073 is hsa-miR-8073, and miR-79 77 is hsa-miR-7977 and miR-1231 is hsa-miR-1231 , miR-6799-5p is hsa-miR-6799-5p, and miR-6 15-5p is hsa-miR-615-5p, and miR-4450 is hsa-miR -4450, and miR-6726-5p is hsa-miR-6726-5p; miR-6875-5p is hsa-miR-6875-5p, and miR-4734 is hsa-miR-4734 and miR-16-5p miR-602 is hsa-miR-602, and miR-4651 is hsa-m iR-4651, miR-8069 is hsa-miR-8069, and miR- 1238-5p is hsa-miR-1238-5p, and miR-6880-5p is h sa-miR-6880-5p and miR-8072 is hsa-miR-8072 miR-4723-5p is hsa-miR-4723-5p, and miR-47 32-5p is hsa-miR-4732-5p, and miR-6125 is hsa-mi miR-6125, miR-6090 is hsa-miR-6090, and miR-7 114-5p is hsa-miR-7114-5p, and miR-564 is hsa-mi miR-564, miR-451a is hsa-miR-451a, and miR-31 35b is hsa-miR-3135b, and miR-4497 is hsa-miR-44 97, miR-4665-5p is hsa-miR-4665-5p, and miR -3622a-5p is hsa-miR-3622a-5p, and miR-6850-5 p is hsa-miR-6850-5p and miR-6821-5p is hsa-miR -6821-5p, miR-5100 is hsa-miR-5100, and miR -6872-3p is hsa-miR-6872-3p, and miR-4433-3p is hsa-miR-4433-3p and miR-1227-5p are hsa-miR-1 227-5p, miR-3188 is hsa-miR-3188, and miR-7 704 is hsa-miR-7704, and miR-3185 is hsa-miR-318 5, miR-1908-3p is hsa-miR-1908-3p, and miR- 6781-5p is hsa-miR-6781-5p and miR-6805-5p is h sa-miR-6805-5p and miR-8089 is hsa-miR-8089 miR-665 is hsa-miR-665 and miR-4486 is hsa-m iR-4486 and miR-6722-3p is hsa-miR-6722-3p miR-1260a is hsa-miR-1260a, and miR-4707-5p is hsa-miR-4707-5p, and miR-6741-5p is hsa-miR- 6741-5p, miR-1260b is hsa-miR-1260b, and mi R-1246 is hsa-miR-1246, and miR-6845-5p is hsa-m iR-6845-5p and miR-4638-5p are hsa-miR-4638-5 p, miR-6085 is hsa-miR-6085, and miR-1228-3 p is hsa-miR-1228-3p, and miR-4534 is hsa-miR-45 34, miR-5585-3p is hsa-miR-5585-3p, and miR -4741 is hsa-miR-4741, and miR-4433b-3p is hsa-m iR-4433b-3p and miR-197-5p are hsa-miR-197-5p , miR-718 is hsa-miR-718, and miR-4513 is hsa- miR-4513 and miR-4446-3p are hsa-miR-4446-3p. miR-619-5p is hsa-miR-619-5p, and miR-6816 -5p is hsa-miR-6816-5p, and miR-6778-5p is hsa-m iR-6778-5p, miR-24-3p is hsa-miR-24-3p , miR-1915-3p is hsa-miR-1915-3p, and miR-4665 -3p is hsa-miR-4665-3p, and miR-4449 is hsa-miR- 4449, miR-6889-5p is hsa-miR-6889-5p, and m iR-486-3p is hsa-miR-486-3p, and miR-7113-3p is hsa-miR-7113-3p and miR-642a-3p are hsa-miR-6 42a-3p, miR-7847-3p is hsa-miR-7847-3p , miR-6768-5p is hsa-miR-6768-5p, and miR-1290 is hsa-miR-1290 and miR-7108-5p is hsa-miR-710 8-5p, miR-92b-5p is hsa-miR-92b-5p, and miR -663b is hsa-miR-663b, and miR-3940-5p is hsa-mi miR-3940-5p, miR-4467 is hsa-miR-4467, and mi R-6858-5p is hsa-miR-6858-5p, and miR-4417 is hs a-miR-4417, miR-3665 is hsa-miR-3665, m iR-4736 is hsa-miR-4736, and miR-4687-3p is hsa- miR-4687-3p and miR-1908-5p are hsa-miR-1908- 5p, miR-5195-3p is hsa-miR-5195-3p, and miR -4286 is hsa-miR-4286, and miR-3679-3p is hsa-mi miR-3679-3p and miR-6791-5p are hsa-miR-6791-5p , miR-1202 is hsa-miR-1202, and miR-3656 is hs a-miR-3656 and miR-4746-3p is hsa-miR-4746-3 p, miR-3184-5p is hsa-miR-3184-5p, and miR- 3937 is hsa-miR-3937 and miR-6515-3p is hsa-miR -6515-3p, miR-6132 is hsa-miR-6132, and miR -187-5p is hsa-miR-187-5p, and miR-7111-5p is hs a-miR-7111-5p and miR-5787 is hsa-miR-5787 and miR-6779-5p is hsa-miR-6779-5p, and miR- 4516 is hsa-miR-4516 and miR-4649-5p is hsa-miR -4649-5p, miR-760 is hsa-miR-760, and miR-3 162-5p is hsa-miR-3162-5p, and miR-3178 is hsa-m iR-3178, miR-940 is hsa-miR-940, and miR-42 71 is hsa-miR-4271, and miR-6769b-5p is hsa-miR- 6769b-5p, miR-4508 is hsa-miR-4508, and miR -6826-5p is hsa-miR-6826-5p, and miR-6757-5p is hsa-miR-6757-5p and miR-3131 and miR-1343-3p is hsa-miR-1343-3p.

[0462] In a preferred embodiment of the method of the present invention, specifically, nucleic acids (specifically, protease inhibitors) probe or primer) is a polynucleotide shown in (a) to (e) below: (a) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide consisting of the base sequence in which u is replaced by t, a variant thereof, or a fragment thereof containing 15 or more consecutive bases, (b) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478; cleotide, (c) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding A polynucleotide consisting of a base sequence complementary to the base sequence in which u is t. a fragment thereof containing 15 or more consecutive bases, (d) a nucleotide sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or the corresponding a polynucleotide comprising a base sequence complementary to the base sequence in which u is t , and (e) A polynucleotide that binds to any one of the polynucleotides (a) to (d) under stringent conditions. hybridizing polynucleotides, is selected from the group consisting of:

[0463] The method of the present invention further includes miR-6808-5p, miR-6774-5p, miR -4656, miR-6806-5p, miR-1233-5p, miR-328-5p , miR-4674, miR-2110, miR-6076, miR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR-638, miR-28 61, miR-371a-5p, miR-211-3p, miR-1273g-3p, m iR-1203, miR-122-5p, miR-4258, miR-4484, miR -4648, miR-6780b-5p, miR-4516, miR-4649-5p, miR-760, miR-3162-5p, miR-3178, miR-940, miR -4271, miR-6769b-5p, miR-4508, miR-6826-5p, miR-6757-5p, miR-3131, and miR-1343-3p Nucleic acids capable of specifically binding to at least one or more polynucleotides can be used. Cut.

[0464] In a preferred embodiment, such nucleic acids specifically comprise miR-6808-5p. sa-miR-6808-5p and miR-6774-5p are hsa-miR-67 74-5p, miR-4656 is hsa-miR-4656, and miR-68 06-5p is hsa-miR-6806-5p, and miR-1233-5p is hsa -miR-1233-5p and miR-328-5p is hsa-miR-328-5 p, miR-4674 is hsa-miR-4674, and miR-2110 is h sa-miR-2110, and miR-6076 is hsa-miR-6076; miR-3619-3p is hsa-miR-3619-3p, and miR-92a-2 -5p is hsa-miR-92a-2-5p, and miR-128-1-5p is hsa -miR-128-1-5p, and miR-638 is hsa-miR-638; miR-2861 is hsa-miR-2861, and miR-371a-5p is hsa -miR-371a-5p, and miR-211-3p is hsa-miR-211-3 p, miR-1273g-3p is hsa-miR-1273g-3p, and mi R-1203 is hsa-miR-1203, and miR-122-5p is hsa-mi miR-122-5p, miR-4258 is hsa-miR-4258, and miR -4484 is hsa-miR-4484, and miR-4648 is hsa-miR-4 648, and miR-6780b-5p is hsa-miR-6780b-5p miR-4516 is hsa-miR-4516, and miR-4649-5p is hsa-miR-4649-5p and miR-760 miR-3162-5p is hsa-miR-3162-5p, and miR-317 8 is hsa-miR-3178 and miR-940 is hsa-miR-940 , miR-4271 is hsa-miR-4271, and miR-6769b-5p is h sa-miR-6769b-5p and miR-4508 is hsa-miR-4508 , miR-6826-5p is hsa-miR-6826-5p, and miR-6 757-5p is hsa-miR-6757-5p, and miR-3131 is hsa-m iR-3131, and miR-1343-3p is hsa-miR-1343-3 p.

[0465] Furthermore, in a preferred embodiment, specifically, such a nucleic acid is selected from the group consisting of the following (f) to (j) ) a polynucleotide shown in (f) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide consisting of the base sequence in which u is t, a variant thereof, a derivative thereof, or is a fragment containing 15 or more consecutive bases, (g) a polynucleotide comprising a nucleotide sequence represented by any one of SEQ ID NOs: 126 to 148; (h) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide consisting of a base sequence complementary to the base sequence in which u is t, and a variant thereof a fragment thereof containing 15 or more consecutive bases, (i) a base sequence represented by any one of SEQ ID NOs: 126 to 148, or the base sequence a polynucleotide comprising a base sequence complementary to the base sequence in which u is t; and (j) A method for detecting a polynucleotide that is hybridized with any one of the polynucleotides (f) to (i) under stringent conditions. hybridizing polynucleotides, is selected from the group consisting of:

[0466] The specimens used in the method of the present invention include biological tissues of subjects (preferably biliary tissues), Examples of specimens include those prepared from body fluids such as blood, serum, plasma, and urine. The RNA-containing sample prepared from the tissue and the polynucleotides prepared from the sample are included. Samples containing methicone, body fluids such as blood, serum, plasma, and urine, and part or all of the subject's biological tissue These are tissues collected by iopsy or extracted by surgery, etc. , a sample can be prepared for measurement.

[0467] As used herein, a subject refers to a mammal, such as, but not limited to, a human, monkey, mouse, rat, etc. and preferably humans.

[0468] In the method of the present invention, the steps can be changed depending on the type of specimen to be measured. can.

[0469] When RNA is used as the measurement target, biliary tract cancer (cells) can be detected using, for example, the following steps: Steps (a), (b) and (c): (a) RNA prepared from a subject's sample or a complementary polynucleotide transcribed therefrom A step of combining a cDNA with a polynucleotide in a kit or device of the present invention. Top, (b) RNA derived from the sample or synthesized from the RNA bound to the polynucleotide cDNA is subjected to hybridization using the polynucleotide as a nucleic acid probe. or by quantitative RT-PCR using the above polynucleotide as a primer. measuring by (c) Based on the results of the measurement in (b) above, the presence or absence of biliary tract cancer (expression of genes derived from biliary tract cancer) Evaluating the presence of may include:

[0470] This invention allows the detection, testing, and evaluation of biliary tract cancer (or its resulting gene expression) in vitro. For example, various hybridization techniques can be used to evaluate or diagnose Such hybridization methods include, for example, Northern blotting and Southern blotting. PCR method, RT-PCR method, DNA chip analysis method, in situ hybridization method , Northern hybridization, Southern hybridization, etc. It is possible.

[0471] When using the Northern blot method, the above-mentioned nucleic acid probes that can be used in the present invention are used. By doing so, it is possible to detect and measure the presence or absence of expression of each gene in RNA and its expression level. Specifically, the nucleic acid probe (complementary strand) is irradiated with a radioisotope ( 32 P, 33 P, 35 S Label with a fluorescent substance or the like, and transfer it to a nylon membrane or the like according to the usual method. After hybridization with RNA from the tissue of the subject, the D The signal derived from the label (radioisotope or fluorescent substance) of the NA / RNA duplex is emitted. X-ray detector (BAS-1800II (Fuji Photo Film Co., Ltd.), etc.) is detected using a fluorescence detector (e.g., STORM 865 (GE Healthcare)). The measurement method can be exemplified.

[0472] When quantitative RT-PCR is used, the above primers that can be used in the present invention are used. This allows the detection and measurement of the presence or absence of gene expression in RNA and the amount of expression. Specifically, cDNA is prepared from RNA derived from the subject's biological tissue according to a standard method. A pair of primers of the present invention is used as a template to amplify a region of each target gene. - (consisting of the positive and negative strands that bind to the above cDNA) is hybridized with the cDNA to form a normal An example of a method is to perform PCR using the method described above and detect the resulting double-stranded DNA. In addition, as a method for detecting double-stranded DNA, the above PCR can be performed in advance using radioisotopes or fluorescent A method using primers labeled with a substance, PCR products are electrophoresed on an agarose gel The method involves electrophoresis and staining double-stranded DNA with ethidium bromide or similar to detect the produced Double-stranded DNA is transferred to a nylon membrane or the like in the usual way and labeled. The method may include a method of detecting the target nucleic acid by hybridizing it with a nucleic acid probe.

[0473] When nucleic acid array analysis is used, the nucleic acid probe (single-stranded or double-stranded) of the present invention is used as a substrate. Use an RNA chip or DNA chip attached to a solid phase. The area where the nucleic acid probe was attached was called a probe spot, and the area where the nucleic acid probe was not attached was called a blank spot. The gene clusters immobilized on a substrate are generally called nucleic acid chips, nucleic acid arrays, and microchips. DNA or RNA arrays are called DNA or RNA macroarrays. Although arrays and DNA or RNA microarrays are included, the term "chip" is used herein. In this case, all of them are included. Target: Human miRNA Oligo chip (Toray Industries, Inc.) can be used. However, this is not limited to this.

[0474] The measurement of the DNA chip is not limited to, but may be performed by, for example, detecting a signal derived from a label of a nucleic acid probe. Null was detected by an image detector (Typhoon 9410 (GE Healthcare)), 3D-Gene ( Examples of methods for detecting and measuring include a scanner (registered trademark) (Toray Industries, Inc.) It is possible.

[0475] As used herein, "stringent conditions" refers to conditions under which the nucleic acid probe is to a greater extent (e.g., mean background reading + background) than for other sequences. The number of hybridizations to the target sequence is determined by the number of hybridizations (measurements of at least 2 times the standard error of the round measurement). This is a condition.

[0476] Stringent conditions are determined by the conditions for hybridization and subsequent washing. The hybridization conditions are not limited, but may be, for example, 30°C to 60°C. SSC, detergent, formamide, dextran sulfate, blocking agent, etc. The conditions are as follows: 1×SSC is a solution containing 150 mM sodium chloride for 1 to 24 hours. The aqueous solution (pH 7.0) contained 15 mM sodium citrate and 15 mM sodium citrate. Contains SDS (sodium dodecyl sulfate), Triton, or Tween. The redox conditions are preferably 3 to 10×SSC, 0.1 to 1% SD Another condition that defines stringent conditions is the hybridization The post-treatment washing conditions are, for example, 0.5x SSC and 0.1% SDS at 30°C. a solution containing 0.2x SSC and 0.1% SDS at 30°C, and a solution containing 0.0x SSC and 0.1% SDS at 30°C. Examples of suitable conditions include successive washing with 5xSSC solution. It is desirable that the hybridized state with the target positive strand be maintained even after washing under the above conditions. Specifically, such a complementary strand is a strand that is completely complementary to the base sequence of the target positive strand. A strand consisting of a certain base sequence, and a strand having at least 80%, preferably at least 85%, %, more preferably at least 90% or at least 95%, for example at least 98% or An example of a chain is a chain consisting of a base sequence having at least 99% identity.

[0477] Other examples of "stringent conditions" for these hybridizations are See, for example, Sambrook, J. & Russell, D., Molecules lar Cloning, A LABORATORY MANUAL, Cold Sp Ring Harbor Laboratory Press, January 15, 2001 This is described in Volume 1, 7.42-7.45, Volume 2, 8.9-8.17, etc. Can be used in inventions.

[0478] Conditions for carrying out PCR using the polynucleotide fragments in the kit of the present invention as primers Examples of suitable solutions include 10 mM Tris-HCl (pH 8.3), 50 mM KCL, , 1 to 2 mM MgCl2, etc., and the sequence of the primer Examples include treating the enzyme at a temperature 5 to 10°C above the Tm value calculated from the above for 15 seconds to 1 minute. The Tm value can be calculated as follows: Tm value = 2 × (number of adenine residues + number of thymine residues) +4 × (number of guanine residues + number of cytosine residues), etc.

[0479] When quantitative RT-PCR is used, TaqMan (registered trademark) Micro RNA Assays (Life Technologies): LNA (registered trademark) -based MicroRNA PCR (Exiqon): Ncode (registered trademark) miRNA, such as miRNA qRT-PCT kit (Invitrogen) A commercially available measurement kit specially designed for quantitative measurement may also be used.

[0480] The gene expression level can be calculated using, but not limited to, statistical anal ysis of gene expression microarray data( Speed ​​T., Chapman and Hall / CRC), and A begi nner's guide Microarray gene expression data analysis(Causton HC et al., Blackwell p. Statistical processing described in, for example, the publication, can be used in the present invention. For example, the average value of the measurements of the blank spots on the DNA chip is added to the measurement value of the blank spot. Add two times, preferably three times, more preferably six times the standard deviation of the The probe spots with a saturation value can be considered as detection spots. The average value of the spot measurements was considered as the background, and the value of the probe spot measurements was subtracted. The missing values ​​of gene expression levels can be calculated by subtracting the or, preferably, replace it with the minimum gene expression level on each DNA chip. More preferably, it is replaced by a value obtained by subtracting 0.1 from the logarithm of the minimum gene expression level. Furthermore, to eliminate genes with low signals, 20% or more of the number of samples measured should be used. Preferably, 50% or more, more preferably 80% or more, is 2 to the power of 6, preferably 2 Only genes with gene expression levels of 8 or more, more preferably 10 or more, are analyzed. The normalization of gene expression levels can be performed using the following methods: Examples include, but are not limited to, global normalization and quantile normalization (Bolstad, BM et al., 2003, Bio Informatics, Vol. 19, pp. 185-193).

[0481] The present invention also relates to the detection polynucleotides, kits, and devices (e.g., chips) of the present invention. or a combination thereof to measure the expression of a target gene or genes in a sample from a subject. The amount of gene expression was measured, and the amount of gene expression in samples from biliary tract cancer patients and healthy subjects was compared with the teacher sample. A discriminant function was created as follows, and the specimen contained a gene derived from biliary tract cancer and / or Provide a method for determining or assessing non-inclusion.

[0482] That is, the present invention further provides the detection polynucleotides, kits, devices (e.g., For example, a chip) or a combination of these methods can be used to confirm that the sample contains genes derived from biliary tract cancer. Multiple samples known to be determined or evaluated as free of genes derived from biliary tract cancer The first step is to measure the expression level of the target gene (target nucleic acid) in vitro. Discrimination using the measured values ​​of the expression levels of the target genes obtained in the first step as teacher samples. In the second step, the expression level of the target gene in the sample from the subject is calculated based on the first step. The third step is to measure the in vitro activity of the protein obtained in the second step. The measured values ​​of the expression levels of the target genes obtained in the third step are substituted into the discriminant equation, and the Based on the results obtained from the discriminant, it is possible to determine whether the sample contains a gene derived from biliary tract cancer or whether the biliary tract is a fourth step of determining or assessing that the gene is free of cancer-derived genes, The target gene is a detection target contained in the polynucleotide, kit, or device (e.g., chip). The method further provides a method for detecting a target gene by a target polynucleotide, wherein the target gene is detectable by a target polynucleotide. Shah's discriminant analysis, nonlinear discriminant analysis using Mahalanobis distance, neural networks, A discriminant formula can be created using a Support Vector Machine (SVM) Examples include, but are not limited to:

[0483] In linear discriminant analysis, when the boundary between groups is a straight line or a hyperplane, Equation 1 is used as the discriminant. Here, x is the explanatory variable, w is the coefficient of the explanatory variable, and w0 is a constant term.

[0484]

number

[0485] The value obtained from the discriminant equation is called the discriminant score, and it explains the measurements of a newly given data set. The discriminant score is substituted as a variable into the discriminant equation, and the grouping can be determined by the sign of the discriminant score.

[0486] Fisher's discriminant analysis, a type of linear discriminant analysis, is a dimensional analysis suitable for classifying It is a dimension reduction method for selecting data with the same label by focusing on the variance of synthetic variables. By minimizing the variance of the data, a highly discriminative composite variable is constructed (Venables, W. Modern Applied Statistics with S. Fourth edition. Springer, 2002). Fisher's In discriminant analysis, we find the projection direction w that maximizes Equation 2. Here, μ is the mean of the input, n g is the number of data belonging to class g, μ g is the mean of the data inputs belonging to class g. The numerator and denominator are the between-class variance and the within-class variance when the data is projected in the direction of vector w, respectively. The discriminant coefficient w is calculated by maximizing this ratio. i (Kanamori Takafumi et al. "Pattern Recognition", Kyoritsu Shuppan (2009), Richard O. et al., Pattern rn Classification Second Edition., Wiley- Interscience, 2000).

[0487]

number

[0488] The Mahalanobis distance was calculated using Equation 3, which takes into account the correlation of the data. It can be used as a nonlinear discriminant analysis to distinguish groups that are close to each other as belonging groups. , μ is the center vector of each group, S -1 is the inverse of the variance-covariance matrix of the group. The torque is calculated from the explanatory variable x, and the mean vector or median vector can be used. do.

[0489]

number

[0490] SVM is a discriminant analysis method invented by V. Vapnik (The Nature f Statistical Leaning Theory, Springer, 19 95). Specific data items in a data set with known classification groups are used as explanatory variables and classification variables. To correctly classify the dataset into known groups using the target group as the objective variable A boundary surface called a hyperplane is determined, and a discriminant formula for classifying the data is determined using the boundary surface. The discriminant is then assigned the measurements of the newly given data set as explanatory variables. By substituting the value into the discriminant, the grouping can be determined. The result may be the group to be classified, or the probability of being classified into the group to be classified. Distance is also acceptable. In SVM, feature vectors are highly refined as a way to deal with nonlinear problems. A method is known in which a nonlinear transformation is performed to a dimension and a linear discrimination is performed in that space. An expression in which the dot product of two elements in the given space is expressed only in terms of the inputs in the original space. The kernel is called a kernel, and examples of kernels are the linear kernel and RBF (Radial Basis Function). Basis Function kernel and Gaussian kernel. While mapping to a higher dimension using a kernel, we actually avoid computing features in the mapped space. Therefore, it is possible to construct the optimal discriminant, i.e., the discriminant, by calculating only the kernel. For example, Hideki Aso et al., Frontiers of Statistical Science 6, "New Statistics in Pattern Recognition and Learning" Concepts and Methods, Iwanami Shoten (2004), Nello Cristianini et al., S Introduction to VM, Kyoritsu Publishing (2008).

[0491] C-support vector classification, a type of SVM method on(C-SVC) is a method that creates a hyperplane by learning with two groups of explanatory variables and then applies it to unknown data sets. (C. Cortes et al., 1995, Ma Chine Learning, Vol. 20, p273-297).

[0492] An example of calculating a discriminant for C-SVC that can be used in the method of the present invention is shown below. The subjects are divided into two groups: biliary tract cancer patients and healthy subjects. To determine whether or not there is a biliary tract disease, for example, a biliary tissue test can be used.

[0493] Next, a dataset consisting of comprehensive gene expression levels of the two separated serum samples ( We prepared a group of samples (hereinafter referred to as the learning sample group) and identified genes that showed clear differences in gene expression levels between the two groups. The discriminant equation using C-SVC with the explanatory variables and the grouping as the objective variable (for example, -1 and +1) Equation 4 is the objective function to be optimized, where e is the total input vector, and y is The objective variable is a vector of Lagrange multipliers, Q is a positive definite matrix, and C is a matrix used to adjust the constraints. Represents the parameter to be adjusted.

[0494]

number

[0495] Equation 5 is the final discriminant, and the sign of the value obtained by the discriminant indicates the group to which it belongs. where x is the support vector, y is the label indicating the group, and a is the corresponding is the coefficient, b is a constant term, and K is the kernel function.

[0496]

number

[0497] As the kernel function, for example, the RBF kernel defined by Equation 6 can be used. where x is the support vector and γ is the kernel parameter that adjusts the complexity of the hyperplane. vinegar.

[0498]

number

[0499] In addition to these, the specimen from the subject contains the expression of target genes derived from biliary tract cancer. and / or determine or evaluate the absence or presence of the protein, or compare the expression level with a control derived from a healthy subject. As methods for evaluating the data, neural networks, k-nearest neighbors, decision trees, and logistic regressions are used. You can choose a method such as regression analysis.

[0500] The method of the present invention may, for example, comprise the following steps (a), (b) and (c): (a) Tissue containing a biliary tract cancer-derived gene derived from a biliary tract cancer patient and / or a biliary tract derived from a healthy subject Expression level of target genes in tissue samples already known to contain no cancer-derived genes and a detection polynucleotide, kit or device (e.g., DNA chip) according to the present invention. measuring using (b) From the measured values ​​of the expression levels measured in (a), the discriminant equations 1 to 3, 5 and 6 are created. a step of forming (c) measuring the expression level of the target gene in a sample derived from a subject using a detection polynucleotide according to the present invention; (b) The measured values ​​are substituted into the discriminant formula, and based on the results obtained, the specimen is determined to contain the target gene derived from biliary tract cancer. Determine or evaluate whether or not a gene is present in a healthy subject, or compare its expression level with that of a healthy subject. evaluating the results in comparison with a control; Here, x in the formulas 1 to 3, 5 and 6 is an explanatory variable, and Measure a polynucleotide or a fragment thereof selected from the polynucleotides described in the section Specifically, the present invention includes a value obtained by discriminating between biliary tract cancer patients and healthy subjects. The explanatory variables for this purpose are, for example, gene expression levels selected from the following (1) and (2): (1) A base sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478, or a complement thereof The genomic sequence is determined by either DNA containing 15 or more consecutive bases. Gene expression levels in the serum of cancer patients and healthy individuals. (2) A base sequence represented by any one of SEQ ID NOs: 126 to 148 or its complementary sequence In addition, patients with biliary tract cancer measured by DNA containing 15 or more consecutive bases Or gene expression levels in the serum of healthy individuals.

[0501] As described above, it is possible to detect whether a sample derived from a subject contains a gene derived from biliary tract cancer and / or whether it contains a gene derived from biliary tract cancer. As a method for determining or evaluating whether or not a discriminant is present, a discriminant is created using a training sample group. A discriminant is required, and in order to improve the discrimination accuracy of the discriminant, It is necessary to use genes with clear differences in the discriminant.

[0502] Furthermore, it is preferable to determine the genes to be used as explanatory variables in the discriminant equation as follows. First, we compared the comprehensive gene expression levels of the biliary tract cancer patient group and the comprehensive gene expression levels of the healthy control group, which are the learning sample groups. The expression level was used as a data set, and the P value of the t-test, which is a parametric analysis, and the P value of the non-parametric The P value of the Mann-Whitney U test, which is a risk analysis, or the P value of the Wilcoxon test The magnitude of the difference in expression level of each gene between the two groups is calculated using values ​​such as the expression level of each gene.

[0503] The risk rate (significance level) of the P value obtained by the test is, for example, 5%, 1%, or 0.01%. A difference smaller than the mean can be considered statistically significant.

[0504] To correct for the increased probability of type I error due to repeated testing, Correction can be performed by methods such as Bonferroni and Holm (e.g. , Yasushi Nagata et al., "Basics of Statistical Multiple Comparison Methods", Scientist Publishing (2007). For example, the P value obtained by a test is multiplied by the number of times the test is repeated. , i.e., multiplied by the number of genes used in the analysis and compared to the desired significance level to obtain the overall This can reduce the probability of making a type I error.

[0505] In addition, rather than testing, the gene expression levels of the biliary tract cancer patient group and the healthy subject group were compared. The absolute value (fold change) of the expression ratio of the median expression level of each gene was calculated and judged. Genes to be used as explanatory variables in a separate formula may also be selected. A ROC curve was created using gene expression levels, and the AUROC value was used as the explanatory variable for the discriminant equation. The gene to be used may be selected.

[0506] Next, using an arbitrary number of genes with large differences in gene expression levels obtained here, A discriminant that can be calculated using the method above is created. A discriminant that obtains the maximum discriminant accuracy is constructed. For example, we can use the P-value significance level to find a discriminant for every combination of genes. The method of construction and the genes used to create the discriminant equation are selected based on the gene expression level with large differences. There are methods for repeatedly evaluating the number of items by increasing it one by one (Furey TS. et al., Bioinformatics, 2000, Vol. 16, p906-14). In contrast, the gene expression levels of other independent biliary tract cancer patients or healthy individuals were substituted as explanatory variables. The discrimination results of the independent biliary tract cancer patients or healthy subjects to which they belong are calculated. The diagnostic gene set and the discriminant constructed using the diagnostic gene set are independently By evaluating a group of specimens, a diagnostic test that can detect more common biliary tract cancers is Gene sets and methods for discriminating biliary tract cancer can be found.

[0507] In addition, the discriminant performance (generalizability) of the discriminant was evaluated using the split-sample method. That is, it is preferable to divide the dataset into a training sample group and a test sample group, and Gene selection and discriminant formula creation are performed using statistical tests on a group of training samples, and test samples are analyzed using the discriminant formula. Accuracy, sensitivity, and specificity were calculated using the results of group discrimination and the true group to which the test sample group belonged. , and evaluate the discrimination performance. On the other hand, statistical tests are performed using all samples without dividing the dataset. The gene is selected and a discriminant formula is created, and a newly prepared sample is discriminated using the discriminant formula to check the accuracy. Sensitivity and specificity can also be calculated to evaluate discriminant performance.

[0508] The present invention provides a polynucleotide for detection or disease diagnosis that is useful for the diagnosis and treatment of biliary tract cancer, A method for detecting biliary tract cancer using the polynucleotide, and a method for detecting biliary tract cancer using the polynucleotide We provide a kit and device for detecting biliary tract cancer, especially for detecting existing tumor markers CEA and C Selection of diagnostic genes and creation of discriminant equations that show accuracy exceeding that of the A19-9 biliary tract cancer diagnostic method In order to carry out the above, in the method of the present invention, for example, CEA and CA19-9 negative Although it was judged that the patient had a normal brain function, detailed examinations such as computed tomography using contrast agents revealed that the patient had a normal brain function. The genes expressed in the serum from patients who were ultimately found to have biliary tract cancer were By comparing the expression of genes in serum from patients without biliary tract cancer, CEA and It is possible to construct a diagnostic gene set and a discriminant equation that show accuracy exceeding that of CA19-9 and CA19-9.

[0509] For example, the nucleic acid sequence represented by any one of SEQ ID NOs: 1 to 125, 466 to 478 described above one or more of the above polynucleotides based on the base sequence of the above-mentioned nucleotide sequence or its complementary sequence, and optionally a base sequence represented by any one of SEQ ID NOs: 126 to 148, or any combination of one or more of the above polynucleotides based on the complementary sequence of The diagnostic gene set is as follows. Furthermore, the diagnostic result of the tissue diagnosis is Class I biliary tract cancer. The expression levels of the diagnostic gene set in the previous specimen and the specimen derived from a Class II healthy subject were used. As a result, the expression level of the diagnostic gene set of an unknown specimen is measured. By this, it is possible to determine whether an unknown sample contains a biliary tract cancer-derived gene or whether it contains a biliary tract cancer-derived gene. It can distinguish between incomplete and incomplete data with up to 100% accuracy. [Example]

[0510] The present invention will be further illustrated by the following examples. However, the scope of the present invention is not limited to these examples. The present invention is not intended to be limited by the following examples.

[0511] [Reference example 1] <Collection of samples from biliary tract cancer patients and healthy individuals> 100 healthy subjects who gave informed consent and 100 subjects with primary cancer other than the biliary tract 67 patients with biliary tract cancer (1 case of stage IA, 8 cases of stage IB, 8 cases of stage II) For example, 3 cases of stage IIA, 5 cases of stage IIB, 14 cases of stage III, 2 cases of stage IIIB, 1 case of stage IVa, and 25 cases of stage IVb) to Venoject I Serum was collected using vacuum blood collection tubes VP-AS109K60 (Terumo Corporation). Similarly, 50 healthy subjects and 50 non-biliary subjects who gave informed consent were used as the learning sample group. 33 biliary tract cancer patients with no primary cancer (1 stage 0, 2 stage I) For example, one case of stage IA, two cases of stage IB, two cases of stage II, and one case of stage IIA 5 cases, stage IIB 4 cases, stage III 5 cases, stage IV 1 case, stage I For 1 case of Va and 9 cases of stage IVb, blood samples were collected using Benojekt II vacuum blood collection tube VP-AS109 Serum was collected from each using K60 (Terumo Corporation), and they were used as test specimen groups

[0512] <Extraction of total RNA> Using the above learning specimen groups and test specimen groups as specimens, a total of 250 people including 150 healthy individuals and 100 biliary tract cancer patients were used. From 300 μL of serum obtained from each of them Total RNA was obtained using the RNA extraction reagent in the 3D-Gene (registered trademark) RNA extraction reagent from liquid sample kit (Toray Industries, Inc.) according to the protocol defined by the company ple kit (Toray Industries, Inc.) according to the protocol defined by the company Total RNA was obtained according to the protocol defined by the company

[0513] <Measurement of gene expression level> Using the above learning specimen groups and test specimen groups as specimens, a total of 250 people including 150 healthy individuals and 100 biliary tract cancer patients were used. For the total RNA obtained from the serum of these people miRNA was fluorescently labeled using the 3D-Gene (registered trademark) miRNA Labeling kit (Toray Industries, Inc.) according to the protocol (ver2.20) defined by the company Using the 3D-Gene (registered trademark) Human miRNA Oligo chip (Toray Industries, Inc.) equipped with probes having sequences complementary to 2,555 types of miRNAs registered in miRBase release 20 Hybridization between miRNAs in total RNA and probes on the DNA chip and washing after hybridization were performed under stringent conditions according to the protocol defined by the company The DNA chip was scanned using a 3D-Gene (registered trademark) scanner (Toray Industries, Inc.) to acquire images and analyze them using 3D-Gene® Ex The fluorescence intensity was quantified using a Toray Traction system. The gene expression level was calculated by converting the logarithm of the base 2. The blank value was subtracted, and missing values ​​were added to each D The value was replaced by the logarithm of the minimum gene expression level in the NA chip minus 0.1. As a result, comprehensive m The gene expression levels of iRNA were obtained. The statistical analysis was performed using R language 3.0.2 (R Development Core Team (2013). R: A language and environment fo r statistical computing. R Foundation fo r Statistical Computing, URL http: / / www. R-project.org / .) and the MASS package 7.3-30 (Venabl es, WN & Ripley, BD (2002) Modern Applied Statistics with S. Fourth Edition n. Springer, New York. ISBN 0-387-95457- 0).

[0514] [Reference example 2] <Collection of specimens from other cancers and benign diseases> 35 colorectal cancer patients with no cancer in other organs who gave informed consent 37 patients with stomach cancer, 32 patients with esophageal cancer, 38 patients with liver cancer, and patients with benign pancreatic and biliary diseases Venoject II vacuum blood collection tubes VP-AS109K60 (Terumo Corporation) were used from 13 patients. Serum was collected from each patient, and 67 patients with biliary tract cancer (1 case of stage 0, 1 case of stage 1) were included. Stage I in 2 cases, stage IA in 1 case, stage IB in 4 cases, stage II in 8 cases, stage There were 4 cases of stage IIA, 6 cases of stage IIB, 14 cases of stage III, and 1 case of stage IIIB. The study included 25 cases of stage IV and 1 case of stage IVa, as well as 93 healthy subjects. Similarly, the subjects who had not been found to have cancer in other organs after obtaining informed consent were included in the study. 15 colon cancer patients, 13 stomach cancer patients, 18 esophageal cancer patients, 12 liver cancer patients, and Venoject II vacuum blood collection tubes VP-AS109K60 (Telescope) were used for blood collection from eight patients with benign pancreatic and biliary diseases. Serum was collected from each patient using a serum sample taken from 33 biliary tract cancer patients (stage 1) in Reference Example 1. 1 case of stage IA, 6 cases of stage IB, 2 cases of stage II, 4 cases of stage IIA, There were 3 cases of stage IIB, 5 cases of stage III, 1 case of stage IIIB, and 11 cases of stage IV. For example, 57 healthy individuals were combined to form the test sample group. The measurement and analysis of gene expression levels were carried out in the same manner as in Reference Example 1.

[0515] [Example 1] Selection of genetic markers using samples from the learning sample group and single-sample selection using samples from the test sample group Method for evaluating the ability of genetic markers to discriminate biliary tract cancer In this example, a genetic marker for distinguishing biliary tract cancer from healthy subjects was selected from a group of training samples. The genetic markers selected in the test sample group, which is independent of the learning sample group, were determined. We investigated methods to evaluate the biliary tract cancer discrimination performance of each of these.

[0516] Specifically, first, the miRNA expression levels of the training sample group and the test sample group obtained in Reference Example 1 above were These were then combined and normalized using quantile normalization.

[0517] Next, diagnostic genes were selected using the training sample group. To obtain a cross-sectional marker, either the biliary tract cancer patient group or the healthy subject group of the learning sample group was selected. In either case, only genes with gene expression levels of 2 to the power of 6 or higher in 50% or more of the samples were included. Furthermore, we selected genes with statistical significance for discriminating between biliary tract cancer patients and healthy subjects. The P values ​​obtained by two-tailed t-test assuming equal variance for each gene expression level were then compared with Bonn- Frank After the Erroni correction, genes that satisfy p<0.01 are used as explanatory variables in the discriminant equation. The results were obtained as cards and are listed in Table 2.

[0518] In this way, hsa-miR-125a-3p, represented by SEQ ID NOs: 1 to 125, hsa-miR-6893-5p, hsa-miR-204-3p, hsa-miR-4 476, hsa-miR-4294, hsa-miR-150-3p, hsa-miR- 6729-5p, hsa-miR-7641, hsa-miR-6765-3p, hsa -miR-6820-5p, hsa-miR-575, hsa-miR-6836-3p , hsa-miR-1469, hsa-miR-663a, hsa-miR-6075, hsa-miR-4634, hsa-miR-423-5p, hsa-miR-4454 , hsa-miR-7109-5p, hsa-miR-6789-5p, hsa-miR -6877-5p, hsa-miR-4792, hsa-miR-4530, hsa-m iR-7975, hsa-miR-6724-5p, hsa-miR-8073, hsa -miR-7977、hsa-miR-1231、hsa-miR-6799-5p、h sa-miR-615-5p、hsa-miR-4450、hsa-miR-6726- 5p、hsa-miR-6875-5p、hsa-miR-4734、hsa-miR- 16-5p、hsa-miR-602、hsa-miR-4651、hsa-miR-8 069、hsa-miR-1238-5p、hsa-miR-6880-5p、hsa- miR-8072, hsa-miR-4723-5p, hsa-miR-4732-5p hsa-miR-6125, hsa-miR-6090, hsa-miR-7114 5p、hsa-miR-564、hsa-miR-451a、hsa-miR-3135 b、hsa-miR-4497、hsa-miR-4665-5p、hsa-miR-3 622a-5p、hsa-miR-6850-5p、hsa-miR-6821-5p、 hsa-miR-5100, hsa-miR-6872-3p, hsa-miR-443 3-3p、hsa-miR-1227-5p、hsa-miR-3188、hsa-mi R-7704、hsa-miR-3185、hsa-miR-1908-3p、hsa- miR-6781-5p、hsa-miR-6805-5p、hsa-miR-8089 hsa-miR-665, hsa-miR-4486, hsa-miR-6722-3 p、hsa-miR-1260a、hsa-miR-4707-5p、hsa-miR- 6741-5p、hsa-miR-1260b、hsa-miR-1246、hsa-m iR-6845-5p、hsa-miR-4638-5p、hsa-miR-6085、 hsa-miR-1228-3p, hsa-miR-4534, hsa-miR-558 5-3p, hsa-miR-4741, hsa-miR-4433b-3p, hsa-m iR-197-5p, hsa-miR-718, hsa-miR-4513, hsa-m iR-4446-3p, hsa-miR-619-5p, hsa-miR-6816-5 p, hsa-miR-6778-5p, hsa-miR-24-3p, hsa-miR- 1915-3p, hsa-miR-4665-3p, hsa-miR-4449, hsa -miR-6889-5p, hsa-miR-486-3p, hsa-miR-7113 -3p, hsa-miR-642a-3p, hsa-miR-7847-3p, hsa- miR-6768-5p, hsa-miR-1290, hsa-miR-7108-5p 、hsa-miR-92b-5p, hsa-miR-663b, hsa-miR-394 0-5p, hsa-miR-4467, hsa-miR-6858-5p, hsa-mi R-4417, hsa-miR-3665, hsa-miR-4736, hsa-miR -4687-3p, hsa-miR-1908-5p, hsa-miR-5195-3p 、hsa-miR-4286, hsa-miR-3679-3p, hsa-miR-67 91-5p, hsa-miR-1202, hsa-miR-3656, hsa-miR- 4746-3p, hsa-miR-3184-5p, hsa-miR-3937, hsa -miR-6515-3p, hsa-miR-6132, hsa-miR-187-5p 、hsa-miR-7111-5p, hsa-miR-5787 and hsa-miR-6 779-5p genes were identified as bile duct cancer markers for normal subjects.

[0519] Furthermore, using the expression levels of these genes as indicators, Fisher's discriminant analysis was used to identify biliary tract cancer. We created a discriminant to determine the presence or absence of 125 species selected in the training sample group. Among the genes, the newly discovered base sequence represented by any of SEQ ID NOs: 1 to 125 The polynucleotides listed below were entered into Equation 2 to create a discriminant formula, and the accuracy, sensitivity, and specificity were calculated. are shown in Table 3. The discriminant coefficients and constant terms are shown in Table 4.

[0520] The accuracy, sensitivity, and specificity of the test sample group were calculated using the discriminant formula created above, and the selection was made. The discriminatory performance of the determined polynucleotides was verified in independent samples (Table 3). For example, the sequence The expression level measurement of the base sequence shown in number 1 was performed on the learning sample group of healthy subjects (100 people) and biliary tract cancer. When comparing patients (67 people), the gene expression measurements of the biliary tract cancer patient group were higher than those of the healthy control group. The results were significantly lower than those of healthy subjects (50 subjects) in the test sample group (see Figure 2, left). ) and biliary tract cancer patients (33 people) (see Figure 2 right). In other polynucleotides shown in Fig. 1, the gene expression of biliary tract cancer patients was significantly higher than that of healthy controls. The measured values ​​of the current amount were significantly lower (-) or higher (+) (Table 2). Furthermore, for example, the base sequence shown in SEQ ID NO: 1 was verified using a group of human samples. The predictive value for detecting biliary tract cancer was calculated using the threshold (5.69) that discriminated between the two groups set in the training sample group. The results showed 33 true positives, 49 true negatives, 1 false positive, and 0 false negatives. The detection performance was 99% accuracy, 100% sensitivity, and 98% specificity. The detection performance of all polynucleotides shown in SEQ ID NOs: 1 to 125 was calculated and shown in Table 3. It was written.

[0521] Among the polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 shown in Table 2, For example, SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2 8, 29, 30, 31, 34, 35, 36, 39, 40, 41, 42, 44, 45, 46 , 47, 49, 50, 51, 52, 53, 54, 60, 62, 64, 65, 67, 68, 62 consisting of the base sequences represented by 70, 74, 75, 76, 83, 84, 105, and 107 These polynucleotides had sensitivities of 100%, 97%, and 97%, respectively, in the test specimen group. ,100%,84.8%,90.9%,87.9%,90.9%,66.7%,87.9 %, 93.9%, 75.8%, 72.7%, 72.7%, 75.8%, 63.6%, 78 .8%, 75.8%, 69.7%, 72.7%, 72.7%, 69.7%, 93.9%, 66.7%, 63.6%, 69.7%, 69.7%, 78.8%, 75.8%, 72.7 %, 78.8%, 81.8%, 66.7%, 60.6%, 60.6%, 72.7%, 66 .7%, 60.6%, 63.6%, 81.8%, 60.6%, 69.7%, 60.6%, 78.8%, 69.7%, 63.6%, 63.6%, 60.6%, 72.7%, 63.6 %, 72.7%, 72.7%, 63.6%, 66.7%, 60.6%, 60.6%, 63 .6%, 63.6%, 69.7%, 63.6%, 69.7%, and 60.6%, respectively (Table 3) Here, from the comparative example described later, the sensitivity of the existing marker CEA in the test sample group was 3 The sensitivity of CA19-9 was 59.4% (Table 5). For example, SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 36, 39, 40, 41, 42, 44, 4 5, 46, 47, 49, 50, 51, 52, 53, 54, 60, 62, 64, 65, 67 , 68, 70, 74, 75, 76, 83, 84, 105, 107 The 62 polynucleotides alone surpass the existing blood tumor marker CA19-9 It was proven that the sensitivity can distinguish biliary tract cancer.

[0522] In addition, for example, the bases represented by SEQ ID NOs: 1, 2, 3, 4, 10, 11, 12, 23, and 64 The nine polynucleotide sequences were obtained from the stage 0 and 1 All six biliary tract cancer specimens (including IA and IB) were correctly identified as biliary tract cancer. Therefore, these polynucleotides can detect early stage biliary tract cancer and are useful for early detection of biliary tract cancer. Contributes to early diagnosis.

[0523] Furthermore, these polynucleotides were expressed in the extrahepatic bile duct, intrahepatic bile duct, and The tumors occupying the gallbladder and papilla were correctly identified as biliary tract cancer. Cancer of the lower bile duct and papilla, which are considered to have a poor prognosis, and cancer of the intrahepatic bile duct, which tends to progress without symptoms. was also detected.

[0524] [Example 2] <Evaluation of biliary tract cancer discrimination performance by combining multiple genetic markers using test specimens Pricing Method> In this example, the genetic markers selected in Example 1 were combined to evaluate the ability to discriminate biliary tract cancer. Specifically, the methods for evaluating the nucleotide sequences of SEQ ID NOs: 1 to 125 selected in Example 1 were investigated. A combination of any two of the measured values ​​of the expression level of polynucleotides consisting of the base sequence represented by Fisher's discriminant analysis was performed on 7,750 combinations to determine the presence or absence of biliary tract cancer. Next, the discriminant equation created above was used to determine the accuracy of the test sample group. The discrimination performance of the selected polynucleotides was examined using independent samples. The test was conducted using the above 7,750 combinations of polynucleotide expression measurements. When biliary tract cancer was discriminated from the sample group, for example, the salts represented by SEQ ID NO: 2 and SEQ ID NO: 4 were Using the measured expression level of a polynucleotide consisting of the base sequence, When comparing the healthy subjects (33 people) and biliary tract cancer patients (33 people), the learning sample group showed a significant difference between the healthy subjects and the biliary tract cancer patients. A scatter plot was obtained in which the expression level measurements of the groups were significantly separated (see Figure 3, left). The results were also reproduced in the test sample group (see Figure 3, right). Any two other pairs of measured values ​​of the expression level of a polynucleotide consisting of the base sequence represented by 5 Scatter plot showing significant separation of expression level measurements between healthy subjects and biliary tract cancer patients, even when combined. These results were verified with a test sample group. Regarding the base sequence shown in SEQ ID NO: 4, a function (0 = 5.16x + y + 48.11), the predictive value for detecting biliary tract cancer was calculated. There were 33 true negatives, 48 ​​true negatives, 2 false positives, and 0 false negatives. The accuracy was 98%, the sensitivity was 100%, and the specificity was 96%. The expression level measurement values ​​of polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 The detection performance for all combinations of any two of these was calculated. and a polynucleotide consisting of a base sequence represented by another SEQ ID NO. The 124 combinations of polynucleotides and their detection performance are listed in Table 6. For example, SEQ ID NO: 1 and SEQ ID NO: 7, SEQ ID NO: 1 and SEQ ID NO: 9, SEQ ID NO: 1 and SEQ ID NO: 2 5. Expression of polynucleotides consisting of the base sequences represented by SEQ ID NO: 1 and SEQ ID NO: 66 All combinations of dose measurements showed 100% sensitivity in the test specimen group. The sensitivity of the polynucleotides is higher than that of the existing marker CA19-9 (75.8% from Table 5). The combinations of nucleotide expression measurements were obtained in 6,316 test sample groups. The combination contains at least one of the base sequences 1 to 125 listed in Table 2 obtained in Example 1. That is, in the test sample group, the bases represented by SEQ ID NOs: 1 to 125 were used. Any combination of two of the measured values ​​of the expression level of polynucleotides consisting of the sequence CA19 It was demonstrated that the method can distinguish biliary tract cancer with a sensitivity exceeding -9.

[0525] In addition, the expression level of polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 is measured. Of the 7,750 combinations of any two values, the status of the test sample group was Correctly identify all six biliary tract cancer specimens of grades 0 and 1 (including IA and IB) as biliary tract cancer. There were 1,290 possible combinations of the two pieces. The combination includes at least a polynucleotide consisting of the base sequence represented by SEQ ID NOs: 1 to 125. These polynucleotides have also been used once before to detect early stage biliary tract cancer. This will contribute to the early diagnosis of biliary tract cancer.

[0526] In this way, polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 Expression level measurements of 3, 4, 5, 6, 7, 8, 9, 10 or more Even if these are combined, a marker with excellent sensitivity for detecting biliary tract cancer can be obtained. Regarding the polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 selected in Example 1, The miRNAs were ranked in descending order of P value, which indicates statistical significance, and the top miRNAs were added one by one. The detection performance was calculated using one or a combination of multiple miRNAs. Sensitivity in the sample group was 100% for one miRNA and 100% for two miRNAs. , 100% for 3 miRNAs, 100% for 5 miRNAs, and 10 miRNAs 00%, 100% with 20 miRNAs, 100% with 50 miRNAs, 100% with 100 m The sensitivity of iRNA was 100%. These sensitivities are higher than those of existing blood tumor markers. Therefore, a combination of multiple miRNAs may be an excellent marker for detecting biliary tract cancer. Here, the combination of multiple miRNAs showed statistical significance as described above. Any combination of multiple miRNAs is effective for biliary tract cancer, regardless of whether they are added in order of difference. It can be used to detect

[0527] From these results, it was found that all polynucleotides consisting of the base sequences represented by SEQ ID NOs: 1 to 125 It can be said that tid is an excellent diagnostic marker for biliary tract cancer.

[0528] [Table 2] TIFF2025138727000023.tif248140TIFF2025138727000024.tif252144TIFF2025138727000025.tif108136

[0529] [Table 3] TIFF2025138727000027.tif251159TIFF2025138727000028.tif246151TIFF2025138727000029.tif146154

[0530] [Table 4] TIFF2025138727000031.tif25177TIFF2025138727000032.tif25474TIFF2025138727000033.tif10572

[0531] [Table 5-1] TIFF2025138727000035.tif244120

[0532] [Table 5-2]

[0533] In Table 5, CEA is 5ng / ml or less and CA19-9 is 37U / ml or less. If the value exceeds the threshold, it is marked as "-", and if it exceeds the threshold, it is marked as "+".

[0534] [Table 6] TIFF2025138727000038.tif249146TIFF2025138727000039.tif249149TIFF2025138727000040.tif139150

[0535] [Example 3] <Selection of genetic markers using whole specimens and discrimination of biliary tract cancer using the obtained genetic markers Performance evaluation method> In this example, the samples of the training sample group and the test sample group used in Examples 1 and 2 above were Using all samples, genetic markers were selected and their performance in discriminating biliary tract cancer was evaluated. .

[0536] Specifically, the serum from 100 biliary tract cancer patients and the serum from 150 healthy subjects obtained in Reference Example 1 above were used. Quantile normalization of serum miRNA expression levels Normalized by n. Selection of gene markers to obtain more reliable diagnostic markers. In either the biliary tract cancer patient group or the healthy subject group, more than 50% of the samples showed a mean value of 2 to the power of 6 or higher. Furthermore, we selected only genes with expression levels of 100 or more. To obtain statistical significance for each gene expression level, two-sided regressions were performed assuming equal variance. The P values ​​obtained from the t-test were Bonferroni corrected, and genes satisfying p<0.01 were selected as the discriminant. The genetic markers used as explanatory variables were selected and listed in Table 7. In addition to the genes listed above, hsa-miR-6808, represented by SEQ ID NOs: 126 to 148, -5p, hsa-miR-6774-5p, hsa-miR-4656, hsa-miR -6806-5p, hsa-miR-1233-5p, hsa-miR-328-5p, hsa-...

Claims

1. A kit for detecting biliary tract cancer, comprising a nucleic acid probe capable of specifically binding to a polynucleotide of miR-8069, a biliary tract cancer marker, or its precursor, and / or a primer that specifically recognizes and amplifies the polynucleotide.

2. The kit according to claim 1, wherein the nucleic acid probe or primer comprises one selected from the group consisting of polynucleotides or fragments thereof shown in (a) to (c) below: (a) (1) a polynucleotide consisting of a base sequence represented by SEQ ID NO: 38 or a base sequence complementary to the base sequence in which u is replaced by t, or a fragment thereof containing 15 or more consecutive bases; (2) A polynucleotide or a fragment thereof comprising the polynucleotide or the fragment of (1) above, which contains a deletion, substitution, addition, or insertion of one or two bases. (3) A polynucleotide or a fragment thereof showing 90% or more identity with the base sequence of the polynucleotide or the fragment of (1), or (4) A polynucleotide or a fragment thereof according to any one of (1) to (3), which contains a modified nucleic acid and / or a modified nucleotide. (b) a polynucleotide containing a base sequence complementary to the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; and (c) A polynucleotide that hybridizes under stringent conditions with any one of the following polynucleotides (5) to (8) or fragments thereof: (5) A polynucleotide consisting of the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (6) A polynucleotide or a fragment thereof according to (5), which contains a deletion, substitution, addition, or insertion of one or two bases. (7) A polynucleotide or a fragment thereof according to (5) or (6), which contains a modified nucleic acid and / or a modified nucleotide. (8) A polynucleotide containing the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases.

3. The kit includes miR-125a-3p, miR-6893-5p, miR-4476, miR-4294, miR-150-3p, miR-6729-5p, miR-7641, miR-6765-3p, miR-6820-5p, miR-575, miR-1469, miR-663a, miR-6075, miR-4634, miR-423-5p, miR-4454, miR-7109-5p, miR-6789-5p, miR-6877-5p, miR-4792, miR-4530, miR-7975, miR-6724-5p, miR-8073, miR-7977, miR-1231, miR-6799-5p, miR-615-5p, miR-4450, miR-6726-5p, miR-6875-5p, miR-4734, miR-16-5p, miR-602, miR-4651, miR-1238-5p, miR-6880-5p, miR-8072, miR-4723-5p, miR-4732-5p, miR-6125, miR-6090, miR-7114-5p, miR-564, miR-451a, miR-3135b, miR-4497, miR-3622a-5p, miR-6850-5p, miR-6821-5p, miR-5100, miR-6872-3p, miR-4433-3p, miR-1227-5p, miR-3188, miR-7704, miR-3185, miR-1908-3p, miR-6781-5p, miR-6805-5p, miR-8089, miR-6722-3p, miR-1260a, miR-4707-5p, miR-6741-5p, miR-1260b, miR-1246, miR-6845-5p, miR-4638-5p, miR-6085, miR-1228-3p, miR-4534, miR-5585-3p, miR-4741, miR-4433b-3p, miR-197-5p, miR-718, miR-4513, miR-4446-3p, miR-619-5p, miR-6816-5p, miR-6778-5p, miR-24-3p, miR-1915-3p, miR-4665-3p, miR-4449, miR-6889-5p, miR-486-3p, miR-7113-3p, miR-642a-3p, miR-7847-3p, miR-6768-5p, which are another biliary tract cancer marker.miR-1290, miR-7108-5p, miR-92b-5p, miR-663b, miR-3940-5p, miR-4467, miR-6858-5p, miR-4417, miR-3665, miR-47 36, miR-4687-3p, miR-1908-5p, miR-5195-3p, miR-4286, miR-3679-3p, miR-6791-5p, miR-1202, miR-3656, miR-4746 -3p, miR-3184-5p, miR-3937, miR-6515-3p, miR-6132, miR-187-5p, miR-7111-5p, miR-5787, miR-6779-5p, miR-4516 , miR-4649-5p, miR-760, miR-3162-5p, miR-3178, miR-940, miR-4271, miR-6769b-5p, miR-4508, miR-6826-5p, miR-6 757-5p, miR-3131, and miR-1343-3p; and / or miR-6808-5p, miR-6774-5p, miR-4656, miR-6806-5p, miR-1233-5p, miR- 328-5p, miR-4674, miR-2110, miR-6076, miR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR-638, miR-2861, miR-371a- The kit according to claim 1 or 2, further comprising a nucleic acid probe capable of specifically binding to at least one or more polynucleotides selected from the group consisting of miR-1273g-3p, miR-1203, miR-122-5p, miR-4258, miR-4484, miR-4648, miR-6780b-5p, and precursors thereof, and / or a primer that specifically recognizes and amplifies the polynucleotide.

4. The kit according to claim 3, wherein the nucleic acid probe or primer according to claim 3 comprises one selected from the group consisting of polynucleotides or fragments thereof shown in (d) to (f) below: (d) (9) A polynucleotide consisting of a base sequence complementary to any of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (10) A polynucleotide or a fragment thereof according to (9), which contains a deletion, substitution, addition, or insertion of one or two bases. (11) A polynucleotide or a fragment thereof showing 90% or more identity with the base sequence of the polynucleotide or the fragment of (9), or (12) A polynucleotide or a fragment thereof according to any one of (9) to (11), which contains a modified nucleic acid and / or a modified nucleotide. (e) a polynucleotide containing a base sequence complementary to any of the base sequences represented by SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (f) A polynucleotide that hybridizes under stringent conditions with any one of the following polynucleotides (13) to (16) or fragments thereof: (13) A polynucleotide consisting of a base sequence represented by any one of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or a base sequence in which u is t in the base sequence, or a fragment thereof containing 15 or more consecutive bases; (14) A polynucleotide or a fragment thereof according to (13), which contains a deletion, substitution, addition, or insertion of one or two bases. (15) A polynucleotide or a fragment thereof according to (13) or (14), which contains a modified nucleic acid and / or a modified nucleotide; or (16) A polynucleotide containing a base sequence represented by any one of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or a base sequence in which u is t in the base sequence, or a fragment thereof containing 15 or more consecutive bases.

5. A device for detecting biliary tract cancer, comprising a nucleic acid probe capable of specifically binding to a polynucleotide of miR-8069, a biliary tract cancer marker, or its precursor, and / or a primer that specifically recognizes and amplifies the polynucleotide.

6. The device according to claim 5, wherein the nucleic acid probe or primer comprises a polynucleotide or a fragment thereof selected from the group consisting of the following polynucleotides (a) to (c): (a) (1) a polynucleotide consisting of a base sequence represented by SEQ ID NO: 38 or a base sequence complementary to the base sequence in which u is replaced by t, or a fragment thereof containing 15 or more consecutive bases; (2) A polynucleotide or a fragment thereof comprising the polynucleotide or the fragment of (1) above, which contains a deletion, substitution, addition, or insertion of one or two bases. (3) A polynucleotide or a fragment thereof showing 90% or more identity with the base sequence of the polynucleotide or the fragment of (1), or (4) A polynucleotide or a fragment thereof according to any one of (1) to (3), which contains a modified nucleic acid and / or a modified nucleotide. (b) a polynucleotide containing a base sequence complementary to the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; and (c) A polynucleotide that hybridizes under stringent conditions with any one of the following polynucleotides (5) to (8) or fragments thereof: (5) A polynucleotide consisting of the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (6) A polynucleotide or a fragment thereof according to (5), which contains a deletion, substitution, addition, or insertion of one or two bases. (7) A polynucleotide or a fragment thereof according to (5) or (6), which contains a modified nucleic acid and / or a modified nucleotide. (8) A polynucleotide containing the base sequence represented by SEQ ID NO: 38 or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases.

7. The device is another biliary tract cancer marker, miR-125a-3p, miR-6893-5p, miR-4476, miR-4294, miR-150-3p, miR-6729-5p, miR-7641, miR-6765-3p, miR-6820-5p, miR-575, miR-1469, miR-663a, miR-6075, miR-4634, miR-423-5p, miR-4454, miR-7109-5p, miR-6789-5p, miR-6877-5p, miR-4792, miR-4530, miR-7975, miR-6724-5p, miR-8073, miR-7977, miR-1231, miR-6799-5p, miR-615-5p, miR-4450, miR-6726-5p, miR-6875-5p, miR-4734, miR-16-5p, miR-602, miR-4651, miR-1238-5p, miR-6880-5p, miR-8072, miR-4723-5p, miR-4732-5p, miR-6125, miR-6090, miR-7114-5p, miR-564, miR-451a, miR-3135b, miR-4497, miR-3622a-5p, miR-6850-5p, miR-6821-5p, miR-5100, miR-6872-3p, miR-4433-3p, miR-1227-5p, miR-3188, miR-7704, miR-3185, miR-1908-3p, miR-6781-5p, miR-6805-5p, miR-8089, miR-6722-3p, miR-1260a, miR-4707-5p, miR-6741-5p, miR-1260b, miR-1246, miR-6845-5p, miR-4638-5p, miR-6085, miR-1228-3p, miR-4534, miR-5585-3p, miR-4741, miR-4433b-3p, miR-197-5p, miR-718, miR-4513, miR-4446-3p, miR-619-5p, miR-6816-5p, miR-6778-5p, miR-24-3p, miR-1915-3p, miR-4665-3p, miR-4449, miR-6889-5p, miR-486-3p, miR-7113-3p, miR-642a-3p, miR-7847-3p, miR-6768-5pmiR-1290, miR-7108-5p, miR-92b-5p, miR-663b, miR-3940-5p, miR-4467, miR-6858-5p, miR-4417, miR-3665, miR-47 36, miR-4687-3p, miR-1908-5p, miR-5195-3p, miR-4286, miR-3679-3p, miR-6791-5p, miR-1202, miR-3656, miR-4746 -3p, miR-3184-5p, miR-3937, miR-6515-3p, miR-6132, miR-187-5p, miR-7111-5p, miR-5787, miR-6779-5p, miR-4516 , miR-4649-5p, miR-760, miR-3162-5p, miR-3178, miR-940, miR-4271, miR-6769b-5p, miR-4508, miR-6826-5p, miR-67 57-5p, miR-3131, and miR-1343-3p; and / or miR-6808-5p, miR-6774-5p, miR-4656, miR-6806-5p, miR-1233-5p, miR-3 28-5p, miR-4674, miR-2110, miR-6076, miR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR-638, miR-2861, miR-371a-5 The device according to claim 5 or 6, further comprising a nucleic acid probe capable of specifically binding to at least one or more polynucleotides selected from the group consisting of miR-1273g-3p, miR-1203, miR-122-5p, miR-4258, miR-4484, miR-4648 and miR-6780b-5p, and precursors thereof, and / or a primer that specifically recognizes and amplifies the polynucleotide.

8. The device according to claim 7, wherein the nucleic acid probe or primer according to claim 7 comprises one selected from the group consisting of polynucleotides or fragments thereof shown in (d) to (f) below: (d) (9) A polynucleotide consisting of a base sequence complementary to any of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (10) A polynucleotide or a fragment thereof according to (9), which contains a deletion, substitution, addition, or insertion of one or two bases. (11) A polynucleotide or a fragment thereof showing 90% or more identity with the base sequence of the polynucleotide or the fragment of (9), or (12) A polynucleotide or a fragment thereof according to any one of (9) to (11), which contains a modified nucleic acid and / or a modified nucleotide. (e) a polynucleotide containing a base sequence complementary to any of the base sequences represented by SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or the base sequence in which u is t, or a fragment thereof containing 15 or more consecutive bases; (f) A polynucleotide that hybridizes under stringent conditions with any one of the following polynucleotides (13) to (16) or fragments thereof: (13) A polynucleotide consisting of a base sequence represented by any one of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or a base sequence in which u is t in the base sequence, or a fragment thereof containing 15 or more consecutive bases; (14) A polynucleotide or a fragment thereof according to (13), which contains a deletion, substitution, addition, or insertion of one or two bases. (15) A polynucleotide or a fragment thereof according to (13) or (14), which contains a modified nucleic acid and / or a modified nucleotide; or (16) A polynucleotide containing a base sequence represented by any one of SEQ ID NOs: 1, 2, 4 to 11, 13 to 37, 39 to 50, 52 to 65, 68 to 125, 126 to 148, and 466 to 478, or a base sequence in which u is t in the base sequence, or a fragment thereof containing 15 or more consecutive bases.

9. The device according to any one of claims 5 to 8, which is a device for measurement by hybridization technology.

10. The device of claim 9 , wherein the hybridization technology is a nucleic acid array technology.

11. A method for assessing the presence or absence of biliary tract cancer, comprising measuring the expression level of a target nucleic acid in a specimen from a subject using the kit according to any one of claims 1 to 4 or the device according to any one of claims 5 to 10, and using the measured expression level and a control expression level similarly measured in a healthy subject, assessing in vitro whether the subject is affected with biliary tract cancer or not.

12. The method of claim 11 , wherein the subject is a human.

13. The method of claim 11 or 12, wherein the sample is blood, serum, or plasma.

14. Use of a polynucleotide of miR-8069, its precursor, or its isomiR as a biliary tract cancer marker for assessing the presence or absence of biliary tract cancer.

15. The polynucleotide of the aforementioned miR-8069, its precursor or its isomiR is miR-125a-3p, miR-6893-5p, miR-4476, miR-4294, miR-150-3p, miR-6729-5p, miR-7641, miR-6765-3p, miR-6820-5p, miR-575, miR-1469, miR-663a, miR-6075, miR-4634, miR-423-5p, miR-4454, miR-7109-5p, miR-6789-5p, miR-6877-5p, miR-4792, miR-4530, miR-7975, miR-6724-5p, miR-8073, miR-7977, miR-1231, miR-6799-5p, miR-615-5p, miR-4450, miR-6726-5p, miR-6875-5p, miR-4734, miR-16-5p, miR-602, miR-4651, miR-1238-5p, miR-6880-5p, miR-8072, miR-4723-5p, miR-4732-5p, miR-6125, miR-6090, miR-7114-5p, miR-564, miR-451a, miR-3135b, miR-4497, miR-3622a-5p, miR-6850-5p, miR-6821-5p, miR-5100, miR-6872-3p, miR-4433-3p, miR-1227-5p, miR-3188, miR-7704, miR-3185, miR-1908-3p, miR-6781-5p, miR-6805-5p, miR-8089, miR-6722-3p, miR-1260a, miR-4707-5p, miR-6741-5p, miR-1260b, miR-1246, miR-6845-5p, miR-4638-5p, miR-6085, miR-1228-3p, miR-4534, miR-5585-3p, miR-4741, miR-4433b-3p, miR-197-5p, miR-718, miR-4513, miR-4446-3p, miR-619-5p, miR-6816-5p, miR-6778-5p, miR-24-3p, miR-1915-3p, miR-4665-3p, miR-4449, miR-6889-5p, miR-486-3p, miR-7113-3p, miR-642a-3p, miR-7847-3p,miR-6768-5p, miR-1290, miR-7108-5p, miR-92b-5p, miR-663b, miR-3940-5p, miR-4467, miR-6858-5p, miR-4417, miR -3665, miR-4736, miR-4687-3p, miR-1908-5p, miR-5195-3p, miR-4286, miR-3679-3p, miR-6791-5p, miR-1202, miR-36 56, miR-4746-3p, miR-3184-5p, miR-3937, miR-6515-3p, miR-6132, miR-187-5p, miR-7111-5p, miR-5787, miR-6779-5 p, miR-4516, miR-4649-5p, miR-760, miR-3162-5p, miR-3178, miR-940, miR-4271, miR-6769b-5p, miR-4508, miR-6826 -5p, miR-6757-5p, miR-3131, and miR-1343-3p; and / or miR-6808-5p, miR-6774-5p, miR-4656, miR-6806-5p, miR-123 3-5p, miR-328-5p, miR-4674, miR-2110, miR-6076, miR-3619-3p, miR-92a-2-5p, miR-128-1-5p, miR-638, miR-2861, m The use according to claim 14, wherein the polynucleotide is used as a biliary tract cancer marker for assessing the presence or absence of biliary tract cancer in combination with at least one polynucleotide selected from the group consisting of iR-371a-5p, miR-211-3p, miR-1273g-3p, miR-1203, miR-122-5p, miR-4258, miR-4484, miR-4648 and miR-6780b-5p; and precursors thereof and isomiRs thereof.

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