Application of combined diagnostic marker in tumor postoperative prognosis and postoperative chemotherapy reactivity prediction

Abstract

The invention relates to the technical field of medical diagnosis, in particular to a marker for tumor postoperative prognosis and tumor postoperative chemotherapy reactivity prediction. The invention provides markers Ku80 and Rab7A for tumor postoperative prognosis and / or tumor postoperative chemotherapy reactivity prediction, the test result shows that the prediction of liver cancer tumor postoperative prognosis and / or tumor postoperative chemotherapy reactivity can be realized through combined / co-detection of Ku80 and Rab7A in liver cancer, the prediction result is accurate and reliable, the detection sensitivity is high, and the kit is suitable for clinical application. The important clinical application value is realized.

Description

Technical Field

[0001] The present invention relates to the technical field of medical diagnosis, and particularly to the application of combined diagnostic markers in predicting the prognosis after tumor surgery and the response to postoperative chemotherapy. Background Art

[0002] There are various treatment methods for tumors, involving multiple disciplines. Common clinical treatment methods mainly include: surgical resection, transplantation, radiofrequency ablation, interventional therapy, and targeted immune system therapy, etc. Among them, chemotherapy (hereinafter referred to as "chemotherapy") is an important therapeutic drug for various treatment methods. Taking liver cancer as an example, chemotherapy has significant effects in some liver cancer patients, but most still have poor responses. Among them, interventional therapy (such as TACE and TAI, etc.) is the main chemotherapy implementation means in the treatment process of liver cancer patients, and is an important part of the treatment plan for liver cancer patients during the perioperative period and in the advanced stage. Especially in preventing the recurrence after resection of resectable liver cancer and as the conversion treatment for patients with advanced unresectable liver cancer, it has been proven to effectively extend the overall survival of patients and improve the clinical outcome.

[0003] As one of the main treatment methods for the whole-course management of various tumors, chemotherapy also has an indispensable position in liver cancer. Especially in the perioperative management of resectable liver cancer, the downstaging treatment of unresectable liver cancer, and controlling the progression of the disease, etc., chemotherapy still cannot be replaced by other treatment means. However, there are many liver cancer patients, and not all liver cancer patients can benefit from chemotherapy. Precise screening of the patient population and identifying the liver cancer patient population with good response and strong sensitivity to the existing chemotherapy regimen are feasible solutions to improve chemotherapy. However, there is still no unified and effective diagnostic method for accurately identifying the chemotherapy reactivity of tumors such as liver cancer. Summary of the Invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide the application of combined diagnostic markers in predicting the prognosis after tumor surgery and the response to postoperative chemotherapy.

[0005] The present invention provides markers for predicting the prognosis after tumor surgery and / or the response to postoperative chemotherapy, which include Ku80 and / or Rab7A;

[0006] The solid tumors mainly including liver cancer include but are not limited to adenoma, papilloma, squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, Hodgkin lymphoma, teratoma, and / or liver cancer, etc., and are not limited to the use in the chemotherapy or adjuvant chemotherapy of hematological tumors;

[0007] Furthermore,

[0008] The tumors include various tumors mainly exemplified by liver cancer, but are not limited to the use in the chemotherapy or adjuvant chemotherapy of hematological tumors;

[0009] The chemotherapy includes various chemotherapy treatments mainly based on transcatheter arterial chemoembolization and / or transcatheter arterial chemoinfusion, but is not limited to other forms of chemotherapy such as systemic chemotherapy;

[0010] The markers described in the present invention can not only predict the prognosis after liver cancer surgery, but also predict the reactivity after liver cancer surgery; in the specific embodiments of the present invention, the increased expression of total Ku80 and Rab7A indicates the worst overall survival (OS) and disease-free survival (DFS) after surgery for patients; while the high expression of cytoplasmic Ku80 / Rab7A indicates a better reactivity to adjuvant chemotherapy / TACE. Therefore, at different stages of the liver cancer treatment process, the prediction of the two treatment processes can be achieved by detecting the same marker in different treatment courses. And in the specific embodiments of the invention, it is found that only the markers described in the present invention can simultaneously predict the prognosis after liver cancer surgery and the chemotherapy reactivity after liver cancer surgery, and the correlation between other differentially expressed substances and different treatment processes of liver cancer is low, and the separate and / or simultaneous prediction of the prognosis after liver cancer surgery and the reactivity after liver cancer surgery cannot be achieved.

[0011] Furthermore, the test results of the present invention also show that the combination of Ku80 and Rab7A as markers has better sensitivity and higher accuracy in predicting the prognosis after liver cancer surgery and the chemotherapy reactivity after liver cancer surgery compared with Ku80 or Rab7A alone as markers; in some other embodiments of the present invention, compared with other existing markers, the combination of Ku80 and Rab7A as markers has more accurate prediction results and can achieve the prediction of different treatment processes of liver cancer; specifically, by comparing tumor markers such as AFP, serum albumin / Albumin, alanine aminotransferase / ALT, Barcelona Clinic Liver Cancer staging / BCLC stage, total bilirubin / Tbil, tumor pathological staging / pStage, positive lymph node metastasis / LN positive, multiple tumors / multiple tumor, microvascular invasion / MVI, tumor volume / tumor size, viral hepatitis / viral hepatitis, liver function grading / Child-Pugh grading, and cirrhosis / cirrhosis, etc., it is shown that patients with high expression of Ku80 / Rab7A have better predicted reactivity after chemotherapy.

[0012] In the present invention, it is clarified that the co-detection of Ku80 and Rab7A can be used as a diagnostic molecular means for the sensitivity of TACE after surgery in patients with liver cancer. Among them, after patients with liver cancer undergo radical surgery, patients with high expression of Ku80 and Rab7A in the cytoplasm of cancer cells in tumor samples have the best TACE efficacy after surgery, and TACE after surgery can effectively improve the prognosis of this part of patients. However, patients with low expression of Ku80 and Rab7A in the cytoplasm of cancer cells in tumor samples have the worst TACE efficacy after surgery, and TACE after surgery cannot effectively improve the prognosis of this part of patients. Therefore, other forms of treatment measures should be taken for this part of patients.

[0013] The present invention provides a combined marker, including at least one of other tumor imaging and / or tumor marker tests and / or pathological examinations for assisting in the judgment of tumor progression and the marker described in the present invention.

[0014] Furthermore, the tumor imaging includes at least one of B-ultrasound, MRI, CT, PET-CT, enhanced CT, and / or X-ray tumor imaging;

[0015] The pathological examination / evaluation includes tumor size, tumor number, vascular invasion (including microvascular invasion, Microvascular Invasion / MVI), tumor pathological grade, tumor pathological stage, lymph node metastasis, liver cirrhosis, non-alcoholic / alcoholic fatty liver, etc.;

[0016] The hematological examination includes at least one of prealbumin (PA), albumin, alanine aminotransferase (glutamic pyruvic transaminase, ALT), aspartate aminotransferase (glutamic oxaloacetic transaminase, AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT or GGT), total bile acid (TBA), hyaluronic acid (HA), laminin (LN), type III procollagen peptide, and type IV collagen, and various viral hepatitis markers.

[0017] The tumor marker is selected from programmed death ligand 1, programmed death receptor 1, tumor mutation burden, mismatch repair defect, high microsatellite instability, CD8 + T cell, CD4 +At least one or several of T cells, NK cells, Treg cells, dendritic cells, interferon γ, granzyme, perforin, Foxp3, CXCL9, CXCL10, CXCL11, STAT1, STAT3, JAK1, JAK2, IRF, CCL8, TIGIT, ICOS, ICOS ligand, squamous cell carcinoma antigen (SCC), antigen processing-related transporter TAP1, antigen processing-related transporter TAP2, MHC class II transcriptional activator, β2-microglobulin, PSA, fPSA, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), cancer antigen 125 (CA125), tumor antigen 153 (CA153), cancer antigen 50, carbohydrate antigen 242, β2-microglobulin, ferritin, alpha-L-fucosidase (AFU), abnormal prothrombin (PIVKA-II), neuron-specific enolase or human chorionic gonadotropin.

[0018] The present invention provides the use of the detection reagent of the said marker and / or the said combined marker in the preparation of a product for predicting the prognosis after tumor surgery and / or the chemotherapeutic reactivity after tumor surgery.

[0019] The present invention provides the use of the said marker and / or the said combined marker in the preparation of a product for predicting the prognosis after tumor surgery and / or the chemotherapeutic reactivity after tumor surgery.

[0020] Furthermore,

[0021] The prediction of the prognosis after tumor surgery and / or the chemotherapeutic reactivity after tumor surgery is to determine whether postoperative chemotherapy for tumors can be performed according to the contents of Ku80 and Rab7A in the sample.

[0022] Even further,

[0023] The gold standard for the said determination is:

[0024] Through any relevant means such as molecular pathology, molecular imaging, and cellular immunofluorescence detection targeting Ku80 and Rab7A, it is clarified that:

[0025] When the cytoplasmic expression level of Ku80 in cancer cells is positive (including weakly positive, positive, and strongly positive) and the expression level of Rab7A is positive (including weakly positive, positive, and strongly positive), it is determined that the patient has a good response to chemotherapy and postoperative chemotherapy for tumors can be performed;

[0026] When the cytoplasmic expression level of Ku80 in cancer cells is negative and the expression level of Rab7A is negative, it is determined that the patient has a poor response to chemotherapy and postoperative chemotherapy for tumors cannot be performed.

[0027] In the present invention, the said sample is a blood sample, liver tissue, and / or liver cancer tissue.

[0028] The present invention provides a product for predicting the prognosis after tumor surgery and / or the chemotherapeutic responsiveness after tumor surgery, and the product includes:

[0029] a reagent for detecting the expression level of the biomarker and / or the combined biomarker; and / or

[0030] a kit for detecting the expression level of the biomarker and / or the combined biomarker; and / or

[0031] a probe targeting the biomarker and / or the combined biomarker.

[0032] The probe includes, but is not limited to, an imaging probe.

[0033] Furthermore, the reagent for detecting the expression level includes: a chemiluminescence reagent, an enzyme-linked immunosorbent assay (ELISA) reagent, and / or a liquid chip assay reagent.

[0034] The present invention provides a method for predicting the prognosis after tumor surgery and / or the chemotherapeutic responsiveness after tumor surgery, which includes determining whether chemotherapy can be performed after tumor surgery according to the content of the biomarker and / or the combined biomarker described in the present invention in a sample and / or imaging pictures.

[0035] The chemotherapy after tumor surgery, or postoperative adjuvant chemotherapy, is defined as any treatment regimen using chemotherapeutic drugs for tumor treatment, and the present invention does not limit this.

[0036] In the present invention, the Ku80 and / or Rab7A can be used as biomarkers for predicting the prognosis after tumor surgery and / or the chemotherapeutic responsiveness after tumor surgery; in practical applications, a detection reagent can be used to detect the expression level of Ku80 and / or Rab7A in vitro to achieve the prediction of the prognosis after tumor surgery and / or the chemotherapeutic responsiveness after tumor surgery; meanwhile, in vivo, with the aid of a targeted imaging probe, imaging evaluation before chemotherapy treatment can be performed.

[0037] The present invention provides the application of a combined diagnostic biomarker in predicting the prognosis after tumor surgery and the chemotherapeutic responsiveness after postoperative chemotherapy. The biomarker is Ku80 and Rab7A. The test results of the present invention show that the prediction of the prognosis after liver cancer tumor surgery and / or the chemotherapeutic responsiveness after tumor surgery can be achieved by co-detecting Ku80 and Rab7A. The prediction results are accurate and reliable, the detection sensitivity is high, and it has important clinical application value. Brief Description of the Drawings

[0038] Figure 1Show the relationship between total Ku80 and Rab7A expression and the overall survival rate of HCC patients after surgery. Among them, A shows that total Ku80 is significantly correlated with Rab7A (TCGA data, Pearson r = 0.6477, p < 0.0001); B shows that high expression of total Ku80 in HCC is correlated with poor overall survival rate (TCGA data, Log-rank test, p = 0.013, high Ku80 group vs low Ku80 group; HR = 1.572); C shows that high expression of Rab7A in HCC is correlated with poor overall survival rate (TCGA data, Log-rank test, p = 0.011, high Rab7A group vs low Rab7A group HR = 1.5757); D shows that in the combined analysis, high expression of both Rab7A and total Ku80 indicates the worst overall survival, while low expression of both indicates the best prognosis (TCGA data, p = 0.0234);

[0039] Figure 2 Show typical pictures of low and high expression of Ku80 and Rab7A in immunohistochemical staining of liver cancer tissues (total cell expression level and cytoplasmic expression level). Among them, A shows low expression of Ku80 and Rab7A; B shows high expression of Ku80 and Rab7A, and the scale bar is as shown in the figure;

[0040] Figure 3Show the combined analysis based on the intracellular total Ku80 / Rab7A expression levels and the subgroup analysis of patients. Among them, A shows that high Rab7A expression indicates poor overall survival rate (OS) after surgery in HCC patients (Log-rank test, p = 0.0096, HR = 1.966 in the high Rab7A group vs the low Rab7A group); B shows that high intracellular total Ku80 expression indicates poor overall survival rate (OS) after surgery in HCC patients (Log-rank test, p < 0.0001, HR = 3.550 in the high Ku80 group vs the low Ku80 group); C shows that high Rab7A expression suggests low disease-free survival rate (DFS) after surgery in HCC patients (Log-rank test, p = 0.0187, HR = 1.687 in the high Rab7A group vs the low Rab7A group); D shows that increased intracellular total Ku80 expression indicates low disease-free survival rate (DFS) after surgery in HCC patients (Log-rank test, p < 0.0001, HR = 3.314 in the high Ku80 group vs the low Ku80 group); E shows further combined analysis of the intracellular total Ku80 / Rab7A expression levels and the subgroup analysis of patients. Patients with both reduced intracellular total Ku80 and Rab7A expression levels have better overall survival after surgery, and patients with both increased intracellular total Ku80 and Rab7A expression levels have the worst overall survival after surgery (OS, Log-rank test, p < 0.0001); F shows that patients with both reduced intracellular total Ku80 and Rab7A expression levels have the best disease-free survival after surgery, and patients with both increased intracellular total Ku80 and Rab7A expression levels have poor disease-free survival after surgery (Log-rank test, p < 0.0001) (Log-rank test, p < 0.0001);

[0041] Figure 4High cytoplasmic Ku80 / Rab7A expression predicts better responsiveness to adjuvant chemotherapy after surgery. Among them, A shows that immunohistochemical staining reveals a significant positive correlation between cytoplasmic Ku80 and Rab7A expression levels (Pearson r = 0.3986, p < 0.0001); B shows that in patients with HCC who received adjuvant chemotherapy after surgery, high cytoplasmic Ku80 expression in liver cancer is associated with good disease-free survival (Log-rank test, p < 0.0001, high cytoplasmic Ku80 expression group vs. low cytoplasmic Ku80 expression group HR = 0.2676); C shows that in patients with HCC who received adjuvant TACE after surgery, high cytoplasmic Ku80 expression in liver cancer is associated with good overall survival (Log-rank test, p = 0.0006, high cytoplasmic Ku80 expression group vs. low cytoplasmic Ku80 expression group HR = 0.3260); D shows that in patients with HCC who received adjuvant chemotherapy after surgery, high Rab7A expression is associated with good disease-free survival (Log-rank test, p = 0.0042, high Rab7A expression group vs. low expression group HR = 0.4702); E shows that in patients with HCC who received adjuvant chemotherapy after surgery, high Rab7A expression is associated with good overall survival (Log-rank test, p = 0.01, high Rab7A expression group vs. low expression group HR = 0.4148); F shows that in patients with HCC who received adjuvant chemotherapy after surgery, patients with both high cytoplasmic Ku80 and Rab7A expression have the best disease-free survival, and conversely, patients with both low expression have the worst disease-free survival (Log-rank test, p < 0.0001); G shows that in patients with HCC who received adjuvant chemotherapy after surgery, patients with both high cytoplasmic Ku80 and Rab7A expression have the best overall survival, and conversely, patients with both low expression have the worst overall survival (Log-rank test, p = 0.0018);

[0042] Figure 5 Shows the fluorescence staining and co-localization results of Ku80 / Rab7A in liver cancer tissues with effective and ineffective chemotherapy. Among them, A shows the immunofluorescence staining results of HCC tissues from patients with effective and ineffective chemotherapy (Ku80 / Rab7A / DAPI staining and photography, n = 10 in each group); B shows the statistical analysis of the co-localized fluorescence signals of Ku80 / Rab7A in HCC tissues from patients with effective and ineffective chemotherapy (t-test, n = 10 / group, **** indicates p < 0.0001);

[0043] Figure 6 Shows the ROC curve comparing cytoplasmic Ku80 / Rab7A as a marker with other tumor markers, pathological features, or imaging features that have been reported in the existing literature and may be used to predict the efficacy of chemotherapy. The diagnostic efficacy of cytoplasmic Ku80 / Rab7A expression level in predicting chemotherapy effectiveness is the highest;

[0044] Figure 7 Schematic diagram showing a combined molecular diagnostic strategy of Rab7A and Ku80 for screening liver cancer patients who are effective in postoperative adjuvant chemotherapy. Detailed implementation mode

[0045] The present invention provides the application of a combined diagnostic marker in predicting the prognosis after tumor surgery and the reactivity to postoperative chemotherapy. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those related can obviously make changes or appropriate alterations and combinations to the methods and applications in this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0046] The test materials used in the present invention are all ordinary commercially available products and can be purchased in the market. The present invention will be further described below in conjunction with embodiments:

[0047] Example 1 Application of the combined diagnostic marker of Ku80 and Rab7A in predicting the prognosis after tumor surgery and the reactivity to postoperative chemotherapy

[0048] I. The elevated expression of total Ku80 and Rab7A is an independent risk factor for HCC patients, and the overall survival (OS) and disease-free survival (DFS) of patients are the worst after surgery. Postoperative treatment is urgently needed to improve their survival

[0049] The results of analyzing the TCGA database showed that in the TCGA data, the expression of total Ku80 and Rab7A was positively correlated ( Figure 1 A in, Pearson r = 0.6477, p < 0.0001). The higher the expression of total Ku80 in liver cancer (the total amount expressed in the nucleus and cytoplasm of liver cancer cells), the worse the overall survival rate of HCC patients ( Figure 1 B in, p = 0.013, HR = 1.572). The higher the expression of Rab7A in liver cancer, the worse the overall survival rate of HCC patients ( Figure 1 C in, p = 0.011, HR = 1.5757). Comprehensive analysis showed that the higher the co-expression of total Ku80 and Rab7A (Ku80 / Rab7A), the lower / worse the overall survival rate, and the lower the co-expression of Ku80 / Rab7A, the higher / better the overall survival rate of patients ( Figure 1 D in, p = 0.0234).

[0050] Subsequently, immunohistochemical staining, scoring and clinicopathological analysis were performed. Representative cases of low expression and high expression of the two markers in immunohistochemical staining were shown, and the specific localization of the two in cancer cells in tumor tissues was indicated as Figure 2 shown, as the scoring criterion.

[0051] Based on the scores after IHC staining in the postoperative HCC tissues of patients, the disease-free survival rate and overall survival rate were analyzed by Kaplan-Meier survival curves, as Figure 3 shown. Univariate and multivariate analyses showed that elevated total intracellular Ku80 and Rab7A expression were independent risk factors for HCC patients, and the overall survival (OS) and disease-free survival (DFS) of patients after surgery were the worst.

[0052] Among them, for the analysis of the overall survival rate of patients with individual markers, high expression of Rab7A indicated poor overall survival rate of HCC patients after surgery (OS, Log-rank test, p = 0.0096, high Rab7A group vs low Rab7A group HR = 1.966, Figure 3 A in Figure 3 ); high expression of total intracellular Ku80 also indicated poor overall survival rate of HCC patients after surgery (OS, Log-rank test, p < 0.0001, high total intracellular Ku80 expression group vs low total intracellular Ku80 expression group HR = 3.550, Figure 3 B in

[0053] For the analysis of disease-free survival rate with individual markers, high expression of Rab7A suggested a lower disease-free survival rate of HCC patients after surgery (DFS, Log-rank test, p = 0.0187, high Rab7A group vs low Rab7A group HR = 1.687, Figure 3 C in Figure 3 ), while an increase in the expression level of total intracellular Ku80 indicated a low disease-free survival rate of HCC patients after surgery (DFS, Log-rank test, p < 0.0001, high total intracellular Ku80 expression group vs low total intracellular Ku80 expression group HR = 3.314, Figure 3 D in

[0054] Furthermore, according to the scores of the expression levels of total intracellular Ku80 / Rab7A, combined analysis and subgroup analysis of patients were performed. Patients with both reduced expression levels of total intracellular Ku80 and Rab7A had the best disease-free survival after surgery, and patients with both elevated expression levels of total intracellular Ku80 and Rab7A had the worst disease-free survival after surgery (Log-rank test, p < 0.0001, Figure 3 E in Figure 3 ). Patients with both reduced expression levels of total intracellular Ku80 and Rab7A had the best overall survival after surgery, and patients with both elevated expression levels of total intracellular Ku80 and Rab7A had the worst overall survival after surgery (Log-rank test, p < 0.0001, Figure 3 F in

[0055] Comprehensive analysis showed that the higher the total intracellular expression of Ku80 and Rab7A, the worse the postoperative clinical prognosis, and postoperative treatment (such as adjuvant chemotherapy, etc.) was urgently needed to improve their survival.

[0056] Second, the high expression of cytoplasmic Ku80 / Rab7A predicts better responsiveness to adjuvant chemotherapy and is a molecular-level tumor marker feature indicating the need for postoperative chemotherapy in tumor patients

[0057] Contrary to the above analysis results, the high expression of cytoplasmic Ku80 in HCC cancer cells is actually an independent protective factor. Moreover, the expression level of cytoplasmic Ku80 is significantly correlated with Rab7A (Pearson r = 0.3986, p < 0.0001, Figure 4 in A). Among HCC patients who received adjuvant TACE after surgery, high cytoplasmic Ku80 expression was associated with good disease-free survival (Log-rank test, p < 0.0001, high cytoplasmic Ku80 expression group vs low cytoplasmic Ku80 expression group HR = 0.2676, Figure 4 in B). Among HCC patients who received adjuvant TACE after surgery, high cytoplasmic Ku80 expression was associated with good overall survival (Log-rank test, p = 0.0006, high cytoplasmic Ku80 expression group vs low cytoplasmic Ku80 expression group HR = 0.3260, Figure 4 in C).

[0058] Among HCC patients who received adjuvant TACE after surgery, high Rab7A expression was associated with good disease-free survival (Log-rank test, p = 0.0042, high Rab7A expression group vs low expression group HR = 0.4702, Figure 4 in D), and among HCC patients who received adjuvant TACE after surgery, high Rab7A expression was associated with good overall survival (Log-rank test, p = 0.01, high Rab7A expression group vs low expression group HR = 0.4148, Figure 4 in E).

[0059] Further combined analysis and subgroup analysis results showed that among HCC patients who received adjuvant TACE after surgery, patients with high expression of both cytoplasmic Ku80 and Rab7A had the best disease-free survival. On the contrary, patients with low expression of both had the worst (Log-rank test, p < 0.0001, low expression group vs high expression group HR = 6.8, 95% confidence interval 3.32 - 13.93, Figure 4In F), this data indicates that after HCC surgery, patients with high expression of both cytoplasmic Ku80 and Rab7A who received adjuvant TACE had a 6.8-fold reduction in recurrence rate (the reduction range was 3.32-fold to 13.93-fold). Among patients with HCC who received adjuvant TACE after surgery, patients with high expression of both cytoplasmic Ku80 and Rab7A had the best overall survival. Conversely, patients with low expression of both had the worst survival (Log-rank test, p = 0.0018, low expression group vs high expression group HR = 4.938, 95% confidence interval 2.153 - 11.33, Figure 4 In G), this data indicates that after HCC surgery, patients with high expression of both cytoplasmic Ku80 and Rab7A who received adjuvant TACE had a 4.938-fold increase in overall survival rate compared to patients with low expression of both (the range was 2.153-fold to 11.33-fold).

[0060] To further verify the results, their tissue expression in postoperative samples of liver cancer patients was detected by immunofluorescence staining. It was confirmed that there was obvious co-localization of Ku80 / Rab7A in the cytoplasm of cancer cells in hepatocellular carcinoma (HCC) tissues (number of samples = 10). In addition, in patients with sensitive and effective postoperative chemotherapy, their co-localization increased significantly (TACE, Figure 5 ).

[0061] The results of the ROC curve (Receiver Operating Characteristic curve) further indicated that patients with high expression of both Ku80 / Rab7A had the best diagnostic performance in predicting a good response to chemotherapy after surgery (i.e., no recurrence state after chemotherapy), as Figure 6As shown, the area under the curve (AUC) of the high expression of cytoplasmic Ku80 / Rab7A was 0.808 (95% confidence interval 0.725 - 0.891). In comparison, the diagnostic efficacy of other diagnostic markers for good postoperative responses in patients was poor. For example, the AUC of the tumor marker AFP was 0.457 (95% confidence interval 0.343 - 0.571), the AUC of serum albumin / Albumin was 0.439 (95% confidence interval 0.327 - 0.551), the AUC of ALT was 0.505 (95% confidence interval 0.390 - 0.619), the AUC of the Barcelona Clinic Liver Cancer staging / BCLC stage was 0.468 (95% confidence interval 0.355 - 0.581), the AUC of total bilirubin / Tbil was 0.544 (95% confidence interval 0.430 - 0.658), the AUC of tumor pathological staging / pStage was 0.473 (95% confidence interval 0.361 - 0.586), the AUC of positive lymph node metastasis / LN positive was 0.465 (95% confidence interval 0.353 - 0.578), the AUC of multiple tumors / multiple tumor was 0.505 (95% confidence interval 0.390 - 0.619), the AUC of microvascular invasion / MVI was 0.464 (95% confidence interval 0.350 - 0.579), the AUC of tumor volume / tumor size was 0.570 (95% confidence interval 0.457 - 0.684), the AUC of viral hepatitis / viral hepatitis was 0.507 (95% confidence interval 0.393 - 0.621), the AUC of liver function classification / Child-Pugh classification was 0.500 (95% confidence interval 0.386 - 0.614), and the AUC of cirrhosis / cirrhosis was 0.494 (95% confidence interval 0.380 - 0.609).

[0062] Existing clinical research evidence (including clinical trials and liver cancer diagnosis and treatment guidelines from various countries) has suggested that the five-year recurrence rate after surgical resection of liver cancer is as high as 70%. After grouping patients according to the expression levels of the molecular markers diagnosed by the combined detection in the present invention, the five-year recurrence rate of liver cancer patients with high cytoplasmic Ku80 / Rab7A expression was significantly reduced to less than 40% after postoperative chemotherapy. Therefore, the combined diagnosis of the co-expression level of Ku80 / Rab7A in cancer cell cytoplasm in the present invention is a good diagnostic indicator and means for screening liver cancer and other tumor patients for postoperative / adjuvant chemotherapy, etc.

[0063] Currently, there is no international standard adjuvant treatment plan to reduce the recurrence after liver cancer surgery. The reports on the improvement of the prognosis of patients with various treatments vary. The reason is still the lack of a diagnostic method that can clearly diagnose and identify appropriate specific treatment measures. In addition, undifferentiated postoperative treatment can cause side effects, such as repeated chemotherapy leading to aggravated liver damage and worse prognosis of patients. Therefore, with the diagnostic method in this patent, the high expression of cytoplasmic Ku80 / Rab7A in HCC tissues indicates a better treatment effect for patients with adjuvant TACE. The combined molecular diagnostic strategy of Rab7A and Ku80 can effectively screen out liver cancer patients who are effective in postoperative adjuvant TACE chemotherapy( Figure 7 ).

[0064] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A marker for predicting the prognosis of tumors after surgery and / or the responsiveness of tumors to chemotherapy after surgery, characterized in that: Including Ku80 and / or Rab7A.

2. The marker according to claim 1, characterized in that The tumors include tumors mainly consisting of liver cancer.

3. The marker according to claim 1 or 2, characterized in that The chemotherapy includes various types of chemotherapy drugs mainly including hepatic artery embolization chemotherapy and / or transcatheter hepatic artery infusion chemotherapy.

4. A combined marker, characterized in that It includes at least one of other tumor imaging and / or tumor marker tests and / or pathological examinations for assisting in judging the tumor progression and the markers described in claim 1 or 2.

5. Use of the marker according to any one of claims 1 to 3 and / or the combined marker according to claim 4 in the preparation of a product for predicting the prognosis of tumor surgery and / or the responsiveness of tumor surgery chemotherapy.

6. The use according to claim 5, characterized in that: The prediction of the postoperative prognosis of the tumor and / or the responsiveness to postoperative chemotherapy of the tumor is to determine whether postoperative chemotherapy of the tumor can be performed based on the content of Ku80 and Rab7A in the sample.

7. The use according to claim 5 or 6, characterized in that: The criteria for judgment are: Through molecular pathology, molecular imaging, cell immunofluorescence detection and any other relevant means targeting Ku80 and Rab7A, it is clear that: The positive expression of Ku80 in the cancer cell cytoplasm and the positive expression of Rab7A indicate that the patient has a good response to chemotherapy and can undergo chemotherapy after tumor surgery; The negative expression of Ku80 in the cancer cell cytoplasm and the negative expression of Rab7A indicated that the patient had a poor response to chemotherapy and could not undergo postoperative chemotherapy.

8. The use according to claim 6, characterized in that: The sample is a blood sample, liver tissue and / or liver cancer tissue.

9. A product for predicting the prognosis of tumors after surgery and / or the responsiveness to chemotherapy after surgery, characterized in that: include: A reagent for detecting the expression level of the marker according to any one of claims 1 to 3 and / or the combined marker according to claim 4; and / or A kit for detecting the expression level of the marker according to any one of claims 1 to 3 and / or the combined marker according to claim 4; and / or A probe targeting the marker according to any one of claims 1 to 3 and / or the combined marker according to claim 4.

10. The product according to claim 9, characterized in that The reagents for detecting expression levels include: chemiluminescence reagents, enzyme labeling reagents and / or liquid chip detection reagents.

11. A method for predicting the prognosis of tumors after surgery and / or the responsiveness to chemotherapy after tumor surgery, characterized in that: Including judging whether chemotherapy after tumor surgery can be performed based on the content of at least one of the following A) to B) in the sample and / or imaging images: A), the marker according to any one of claims 1 to 3; B) The combined marker according to claim 4.

Images