Establishment and use of a bladder cancer biomarker combination

Abstract

The application belongs to the field of biological detection and relates to a kind of establishment and clinical use for bladder cancer prognosis risk marker.The marker is composed of 23 mutant genes of AHNAK2,RYR2,USH2A,DCHS2,BRCA2,RP1L1,FBN2,ZFYVE26,ANK1,NCOR1,F8,WNK1,IGSF10,COL11A1,RANBP2,MED1,FANCM,MYO18B,ZNFX1,MROH2B,AUTS2,CNOT1,COL5A1.The application screens reliable and independent biomarker which can effectively predict the clinical prognosis of bladder patients.Provides a best mutant marker as potential prognostic biomarker and prediction model for combined chemotherapy response of bladder patients.

Description

Technical Field

[0001] This invention belongs to the field of biological detection and relates to the establishment and clinical application of a prognostic risk marker for bladder cancer. Background Technology

[0002] Bladder cancer (BC) is the most common malignant tumor of the urinary tract and the ninth leading cause of cancer-related death worldwide. It ranks fourth among the most common cancers in men, with an estimated 17,670 deaths (12,870 in men and 4,800 in women) and 80,470 new cases (61,700 in men and 18,770 in women) in 2019. Clinically, bladder cancer can be classified into non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). Despite early prevention and intervention, many MIBC patients remain at high risk of recurrence and death. Although the prognosis of NMIBC is better than that of MIBC, the high risk of recurrence in NMIBC patients cannot be ignored. Therefore, screening for a new, potentially reliable prognostic indicator to predict the survival of bladder cancer patients is imperative.

[0003] The widely accepted theory of gene mutation in the scientific community to date posits that mutations at the gene level are the primary cause of cancer. It has been reported that in most cancers, including bladder cancer, hundreds to thousands of variations exist in both partial and complete genomic sequences of the tumor. Similarly, in recent years, with the deepening of cancer research, an increasing number of reports indicate that gene mutations play a significant role in cancer. Previous studies have identified several frequently mutated genes in bladder cancer, including TP53, FGFR3, RB1, PIK3CA, KDM6A, CREBBP, and EP300. Some gene variations have been shown to be associated with susceptibility to bladder cancer. However, due to the high heterogeneity of cancer, including a large number of random genomic alterations, it is necessary to continuously study and evaluate the utility of gene mutations. Summary of the Invention

[0004] In view of the shortcomings of existing technologies, this invention provides a novel set of combined mutated genes associated with the survival of bladder cancer patients, serving as an independent and highly accurate indicator for evaluating bladder cancer patient survival. The risk score, combined with conventional clinical characteristics, has high clinical application value.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] The biomarker described in this invention consists of 23 mutant genes: AHNAK2, RYR2, USH2A, DCHS2, BRCA2, RP1L1, FBN2, ZFYVE26, ANK1, NCOR1, F8, WNK1, IGSF10, COL11A1, RANBP2, MED1, FANCM, MYO18B, ZNFX1, MROH2B, AUTS2, CNOT1, and COL5A1.

[0007] Furthermore, the biomarker is a biomarker of mutated genes in human bladder cancer tissue.

[0008] The use of AHNAK2, RYR2, USH2A, DCHS2, BRCA2, RP1L1, FBN2, ZFYVE26, ANK1, NCOR1, F8, WNK1, IGSF10, COL11A1, RANBP2, MED1, FANCM, MYO18B, ZNFX1, MROH2B, AUTS2, CNOT1, and COL5A1 as prognostic risk markers for bladder cancer in the preparation or screening of bladder cancer detection reagents.

[0009] The bladder cancer mutation gene biomarker described in this invention is used for at least one of bladder cancer diagnosis, treatment selection, and prognosis.

[0010] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0011] The embodiments of this invention investigated the potential use of tissue as a biomarker for bladder cancer. This invention provides novel, highly sensitive, and specific biomarkers for the diagnosis and prognosis of bladder cancer, possessing significant clinical application and promotional value. Attached Figure Description

[0012] Figure 1 (A) Kaplan-Meier survival curves and (B) ROC curves of mutational biomarkers associated with prognosis in bladder cancer patients from the TCGA database.

[0013] Figure 2 Risk scores and clinical characteristics were analyzed using univariate and multivariate Cox analyses.

[0014] Figure 3 The correlation between risk scores and efficacy in patients treated with gemcitabine in combination with cisplatin. (A) Risk scores of patients with complete remission (CR) / partial remission (PR) and stable disease (SD) / progressive disease (PD). (B) Objective responses of patients with high-risk and low-risk scores. Detailed Implementation

[0015] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0016] Example 1: Identification of survival-related mutated genes in bladder cancer patients

[0017] This invention obtains mutation data, gene expression profiles, and corresponding clinical information of bladder cancer patients from the TCGA (http: / / cancergenome.nih.gov) and UCSC Xena (https: / / tcga.xenahubs.net) databases. Univariate and multivariate Cox regression analyses are used to construct a prognostic mutation biomarker and risk score model formula: Risk Score = β1 gene 1 * gene 1 mutation status + β2 gene 2 * gene 2 mutation status + ... + βn gene * gene mutation status. Where β is the coefficient of each mutated gene in the multivariate Cox regression analysis. "0" indicates that the gene has not mutated, and "1" indicates that the gene has mutated, including Missense Mutation, In Frame Del, Silent, RNA, Splice Site, FrameShift Del, Frame Shift Ins, and Transition Start Site.

[0018] Risk scores for 23 mutation biomarkers were calculated for each patient. The distribution of mutation risk scores, survival status of bladder patients, and mutated gene alterations were obtained. Using the median risk score as the cutoff point, bladder patients were divided into a high-risk group (n=201) and a low-risk group (n=202). Kaplan-Meier curves showed that patients with high-risk scores had shorter survival and poorer prognosis (P<0.0001). Figure 1 A). The ROC curves over time showed that the predictive sensitivity and specificity of the mutation biomarker at 1 year, 3 years, 5 years, and 10 years were 0.893, 0.896, 0.916, and 0.965, respectively. Figure 1 B). In summary, this mutation biomarker has high accuracy and is a potential new indicator for assessing patient survival.

[0019] Example 2: Mutation biomarkers are an independent prognostic indicator

[0020] Univariate and multivariate Cox proportional hazards regression analyses were performed on bladder mutated genes using R software package 3.5.1 (https: / / www.r-project.org / , v3.5.1) to further determine whether the risk score was an independent risk factor for the clinical outcome of bladder patients. Univariate Cox analysis showed that risk score, TNM, T stage, N stage, tumor status, and lymphovascular invasion were significantly associated with patient prognosis. Figure 2 Furthermore, multivariate Cox analysis identified risk score and tumor status as independent risk factors for prognosis in bladder patients. Figure 2 These results indicate that, after adjustment for routine clinical characteristics, mutation biomarkers remained independently associated with overall survival.

[0021] Example 3: Mutation biomarkers are associated with improved efficacy of combination chemotherapy

[0022] The patient received gemcitabine plus cisplatin. Patients with objective response (complete or partial response, CR / PR) had a lower risk score than patients without response (stable or progressive disease, SD / PD) (P = 0.0152). Figure 3 A). Similarly, patients with low-risk scores had a higher objective response rate (P = 0.0244). Figure 3 B). These results indicate a strong correlation between a decrease in risk score and an increase in objective response rate.

[0023] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A set of mutant gene biomarkers for prognostic risk assessment of bladder cancer, characterized in that, The bladder cancer tissue mutation gene biomarker consists of the following mutated genes: AHNAK2, RYR2, USH2A, DCHS2, BRCA2, RP1L1, FBN2, ZFYVE26, ANK1, NCOR1, F8, WNK1, IGSF10, COL11A1, RANBP2, MED1, FANCM, MYO18B, ZNFX1, MROH2B, AUTS2, CNOT1, and COL5A1, totaling 23 mutated genes.

2. The mutant gene biomarker according to claim 1, characterized in that, The mutant gene biomarkers are human tissue mutant gene biomarkers.

3. The use of the mutant gene biomarker according to claim 1 in the preparation or screening of bladder cancer detection reagents.

4. The use according to claim 3, characterized in that, The bladder cancer detection reagent uses AHNAK2, RYR2, USH2A, DCHS2, BRCA2, RP1L1, FBN2, ZFYVE26, ANK1, NCOR1, F8, WNK1, IGSF10, COL11A1, RANBP2, MED1, FANCM, MYO18B, ZNFX1, MROH2B, AUTS2, CNOT1, and COL5A1 as the detection targets; the detection reagent is a kit and / or a high-throughput chip.

5. The use according to claim 3, characterized in that, The bladder cancer detection reagent is used for at least one of the following: bladder cancer diagnosis, treatment selection, and prognosis.

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