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Genes for molecular typing of hypermutated tumors and their application

A mutant and tumor technology, applied in the determination/testing of microorganisms, biochemical equipment and methods, DNA/RNA fragments, etc., can solve the defects of gene mismatch repair system, microsatellite instability, and can not well prompt immunity Issues such as the response to treatment and the possibility of ultimate benefit to achieve good benefits and good clinical guidance

Active Publication Date: 2020-09-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

However, according to the recent sequencing results of more than 80,000 cases of various tumors, microsatellite instability accounts for the majority but not all of the hypermutated tumors with a large number of gene mutations, and the other majority is caused by mutations in POLE or POLD1. Functional mutations in two genes can cause defects in the gene mismatch repair system in cells, which in turn leads to the emergence of a large number of mutations in tumor cells
The above evidence shows that the existing markers can not well indicate the response of immunotherapy and the possibility of ultimate benefit. It is urgent to screen a better marker to better judge whether tumor patients can benefit from immunotherapy, but considering For the convenience of clinical application, it should include as few indicators as possible and can be completed in one test

Method used

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  • Genes for molecular typing of hypermutated tumors and their application
  • Genes for molecular typing of hypermutated tumors and their application
  • Genes for molecular typing of hypermutated tumors and their application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Genomic DNA Samples and Determination of Tumor Somatic Mutation Sites

[0031] In order to detect the somatic mutation of colorectal cancer, the present invention completed the high-throughput sequencing of 338 colorectal cancer tissue samples in two stages, and completed the high-throughput sequencing of 80 cases of colorectal cancer in the first stage, of which 10 cases For whole genome sequencing, 70 cases for whole exome sequencing. Through the first stage of high-frequency gene analysis, further combining the high-frequency genes in the TCGA database and COSMIC database, and the NCCN guidelines for the diagnosis and treatment of hereditary colorectal cancer, the present invention designed a gene group comprising 524 genes (Table 1), Capture probes targeting this gene group were customized for the second stage of sequencing. In the second phase, the targeted sequencing of 258 colorectal cancer tissue samples was completed using the capture ...

Embodiment 2

[0034] Example 2 Establishment of a gene mutation prognosis prediction model for hypermutated colorectal cancer

[0035] Since the currently approved immunotherapy drugs are mainly aimed at tumor patients with dMMR and MSI‐H, the characteristics of these patients at the genomic level are mainly hypermutations. Tumors with a mutation burden greater than 10 Mut / Mb were defined as hypermutated tumors. Among the 338 cases of colorectal cancer (ZJU data set) in Example 1, 45 cases were determined to be hypermutated. In addition, in order to verify the stability and universality of the model, the present invention downloaded a total of 382 cases of colorectal cancer data from TGCA as independent verification data (TCGA data set), and according to the same standard, 63 cases were designated as hypermutated colorectal cancer. Further, the present invention requires patient data with a follow-up time of more than 24 months for the establishment of a prognostic model, so 45 cases from...

Embodiment 3

[0037] Example 3 Analysis of colorectal cancer from ZJU and TCGA datasets using DOCK2 gene prognostic prediction model

[0038] Since hypermutated and microsatellite unstable colorectal cancers account for about 15% of the total, the number of patients in a single data set is relatively small. In order to further fully demonstrate the beneficial effects of the present invention, the present invention will use the colorectal Integrate the cancer data set, apply the DOCK2 gene prognosis prediction model constructed in Example 2, analyze the hypermutated colorectal cancer in the integrated data set, and distinguish it as DOCK2 wild type according to the mutation status of the DOCK2 gene in each patient in Table 2 group and DOCK2 mutant group, see figure 1 , compared with patients in the DOCK2 wild-type group, the hazard ratio of the DOCK2 mutant group was 1.54 (95% confidence interval = 1.11-2.15, P = 0.019).

[0039] Table 2

[0040]

[0041]

[0042] The TNM staging sta...

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Abstract

The invention discloses a super-mutant type tumor molecule subtype gene capable of distinguishing patients with poor prognosis and good prognosis of super-mutant type colorectal cancer, squamous-cellcarcinoma and skin melanoma. Doctors can be reminded to take different treatment methods for two groups of patients, good benefits can be made through immunotherapy for patients with poor prognosis, and good clinical instruction significances can be made. The invention further discloses a kit for capturing the gene.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a gene for molecular typing of various hypermutated tumors, and the application of the gene in predicting short-term remission and long-term benefit of tumor immunotherapy. Background technique [0002] Malignant tumors have become a global public health problem. In the past three decades, the incidence of cancer has been increasing at an average annual rate of 3%-5%, and cancer has become the number one cause of death for human beings. Surgery, chemotherapy, and radiotherapy are traditional cancer treatments. At present, most early-stage patients can obtain a better prognosis after comprehensive treatment, but these treatments cannot reduce the mortality of all cancer patients. Therefore, it is urgent to develop more effective treatments. Since the New England Journal reported two landmark clinical trials in 2012, immunotherapy has entered a new era of rapid development. Represented...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12Q1/6886C12N15/11
CPCC12Q1/6886C12Q2600/118C12Q2600/156
Inventor 葛维挺胡望雄韩卫东胡涵光蔡文黄彦钦陈丽荣丁克峰郑树
Owner ZHEJIANG UNIV
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