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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：
10003304
负责人：
CHARLES L. SAWYERS
金额：
$ 42.62万
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/10003304
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 PALB2 gene 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 genomic locus 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.

项目总结/摘要 DNA损伤修复（DDR）途径基因中的致病性变异在一部分男性中普遍存在，转移性去势抵抗性前列腺癌（mCRPC），并发生在体细胞和生殖细胞基因组这些异常，主要是导致蛋白质截短的插入和缺失，发生在10- 20%的mCRPC患者。这些变异也发生在较低级别的局限性前列腺癌中，尽管 DDR突变在这些肿瘤中的发生率及其对临床结果、生存率和药物治疗的影响敏感性在很大程度上是未知的。在拟议拨款的其他项目中，DDR基因的特定突变将被识别。项目3的重点将是优先考虑和系统地评估这些突变，使用功能测定、最先进的类器官技术、CRISPR介导的基因编辑和全基因组测序分析。在项目3的目标1中，我们将使用多种前列腺癌细胞系，确定特定的DDR基因突变是有害的还是良性的变异。我们将检验这个假设真正的致病性DDR等位基因与更具侵袭性的肿瘤表型相关，与特定的功能性DNA修复缺陷和药物反应相关。在目标2中，我们将使用基因编辑来将DDR突变引入多种前列腺癌细胞系的内源性遗传基因座中，以提供对特定突变进行更多的生理学评估。在目标3中，我们将分析全基因组序列从前列腺癌，以确定精确的突变签名，这可能导致的损失，特定DDR基因的功能突变。项目3将与调查人员进行广泛合作，项目1和2以及基因组学核心，如所附研究计划所述。