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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：
10495179
负责人：
CHARLES L. SAWYERS
金额：
$ 41.94万
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/10495179
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 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 treatment response 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/文摘