Functional Evaluation and Interpretation of DNA Damage Repair Variants in Prostate Cancer

前列腺癌 DNA 损伤修复变异体的功能评估和解释

基本信息

批准号：
9792982
负责人：
CHARLES L. SAWYERS
金额：
$ 46.6万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9792982
关键词：
Address Alleles Antineoplastic Agents BRCA1 gene BRCA2 gene Benign Biological Assay Biological Markers CHD1 gene CRISPR/Cas technology Cells Chromosomal Stability Clinical Clinical Research Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA DNA Repair Data Defect Disease Drug Exposure Engineering Enrollment Evaluation Fanconi Anemia Complementation Group A Protein Fanconi Anemia-BRCA Pathway Gene Mutation Genes Genetic Genome Genomics Goals Grant Heterozygote Lead Malignant neoplasm of prostate Mediating Missense Mutation Modeling Molecular Mutation Organoids Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Poly(ADP-ribose) Polymerases Prevalence Protein Truncation Radical Prostatectomy Recurrence Research Research Personnel Site Technology Testing Therapeutic Tumor-Derived Variant androgen deprivation therapy base castration resistant prostate cancer design drug response prediction drug sensitivity experience gene repair genetic variant genome analysis genome editing genome sequencing high risk inhibitor/antagonist insertion/deletion mutation loss of function mutation men mutant next generation sequencing patient population patient response prostate cancer cell prostate cancer cell line prostate cancer risk repaired response stability testing tumor whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Pathogenic variants in DNA damage repair (DDR) pathway genes are prevalent in a subset of men with metastatic castration-resistant prostate cancer (mCRPC) and occur in both the somatic and germline genomes. These abnormalities, primarily insertions and deletions resulting in protein truncations, occur in 10– 20% of patients with mCRPC. These variants also occur in lower-grade localized prostate cancers, although the prevalence of DDR mutations in these tumors and their impact on clinical outcome, survival, and drug sensitivity are largely unknown. In other projects of the proposed grant, specific mutations in DDR genes will be identified. The focus of Project 3 will be to prioritize and systematically evaluate these mutations, using a combination of functional assays, state-of-the-art organoid technology, CRISPR-mediated gene editing, and analysis of whole genome sequencing. In Aim 1 of Project 3, we will use multiple prostate cancer cell lines to determine whether specific DDR gene mutations are deleterious or benign variants. We will test the hypothesis that bona fide pathogenic DDR alleles are associated with a more aggressive tumor phenotype and will correlate with specific functional DNA repair defects and drug responses. In Aim 2, we will use gene editing to introduce DDR mutations into the endogenous genetic locus of multiple prostate cancer cell lines to provide a more physiologic assessment of the specific mutations. In Aim 3, we will analyze the whole-genome sequences from prostate cancers to identify precise mutational signatures which may result from loss-of- function mutations in specific DDR genes. Project 3 will have extensive collaborations with the investigators in Projects 1 and 2 and the Genomics Core as outlined in the attached research plan.

项目摘要/摘要 DNA损伤修复中的致病变异（DDR）途径基因普遍存在转移性castration-耐药前列腺癌（MCRPC），在体细胞和种系中发生基因组。这些异常，主要插入和导致蛋白质截断的缺失，发生在10-中 20％的MCRPC患者。这些变体也出现在低级局部前列腺癌中这些肿瘤中DDR突变的患病率及其对临床结果，生存和药物的影响灵敏度在很大程度上未知。在拟议赠款的其他项目中，DDR基因中的特定突变将被识别。项目3的重点将是使用A的优先级和系统地评估这些突变功能测定，最先进的器官技术，CRISPR介导的基因编辑和整个基因组测序的分析。在项目3的AIM 1中，我们将使用多个前列腺癌细胞系来确定特定的DDR基因突变是有害变体还是良性变体。我们将检验假设真正的致病性DDR等位基因与更具侵略性的肿瘤表型相关与特定功能性DNA修复缺陷和药物反应相关。在AIM 2中，我们将使用基因编辑来将DDR突变引入多个前列腺癌细胞系的内源性遗传基因座，以提供对特定突变的更多生理评估。在AIM 3中，我们将分析整个基因组前列腺癌的序列以识别可能导致的精确突变特征，这可能导致特定DDR基因中的功能突变。项目3将与调查人员进行广泛的合作项目1和2以及所附研究计划中概述的基因组核心。