RP-2: Discovery and Characterization of Novel Genes and DNA Repair Pathways Predisposing to Urothelial Cancer

RP-2：易患尿路上皮癌的新基因和 DNA 修复途径的发现和表征

• 批准号: 10226971
• 负责人: Dean F. Bajorin
• 金额: $ 35.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226971
• 关键词: Affect; Age; Age of Onset; Basic Science; Biological Assay; Bladder Neoplasm; Bladder Urothelium; CHEK2 gene; Cancer Patient; Cancer-Predisposing Gene; Candidate Disease Gene; Chromosomal Stability; Clinical; Clinical Sciences; Collection; Consent; DNA; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA Sequence Alteration; DNA analysis; Data; Databases; Development; Disease; Doctor of Philosophy; ERCC2 gene; ERCC3 gene; Epidemiology; Family history of; Family member; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Germ-Line Mutation; Heritability; High Prevalence; Incidence; Inherited; International; Lead; Loss of Heterozygosity; MSH2 gene; MSH6 gene; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methodology; Mismatch Repair; Modernization; Mutation; Nucleotide Excision Repair; Onset of illness; PTEN gene; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Predisposition; Primary Neoplasm; Proteins; RB1 gene; Relative Risks; Reporting; Research Personnel; Resources; Role; Sampling; Susceptibility Gene; Syndrome; System; Technology; Therapeutic; Translating; Urothelium; Validation; Variant; Work; base; body system; brca gene; cancer predisposition; cancer risk; chromosome replication; clinically actionable; cohort; early onset; exome; exome sequencing; gene repair; genetic epidemiology; genome sequencing; genome wide association study; kindred; neoplasm registry; next generation sequencing; novel; proband; repaired; response; tumor; tumor DNA; whole genome

PROJECT SUMMARY/ABSTRACT Bladder (urothelial) cancer has a substantial inherited component, with an estimated heritable fraction of approximately 30%. Genome-wide association studies document an estimate of familial relative risk for urothelial cancer similar to that seen in familial bladder cancer registries (1.37 vs 1.69). Highly penetrant cancer susceptibility genes such as those in the mismatch- repair pathway (eg, MSH2, MSH6) account for only a small fraction of genetic susceptibility to urothelial cancer. There are also numerous reports of multiple-case urothelial cancer kindreds that have not yet been systematically studied using modern sequencing methodologies. Using bait capture next-generation sequencing assays of paired somatic and germline DNA, we showed that that 20% of urothelial cancer patients have moderate- to highly-penetrant known predisposition genes. Approximately 70% of these genes are in DNA damage response gene pathways, genes that predispose for a broad spectrum of non-urothelial cancers. Preliminary data also identified a novel mechanism of bladder cancer susceptibility in a nucleotide excision repair pathway. This project seeks to identify novel urothelial cancer susceptibility genes by genotyping DNA from >480 kindreds demonstrating familial urothelial cancer, ~275 patients with early (≤ age 45) and extremely early (≤ age 30) disease onset, and a selected subset of over 1000 patients in whom urothelial cancer is a component of multiple primary cancers of which one is urothelial cancer. We will utilize next-generation sequencing assays of paired somatic and germline DNA to identify loss of heterozygosity in bladder tumors, as well as interrogation of germline genomes and exomes from familial and early-onset cases to discover putative bladder cancer susceptibility genes. We will assess candidate genes that may contribute to hereditary urothelial cancer in the above-mentioned kindred studies, genes in pathways governing DNA repair, and genes identified in prior genome-wide association studies. For both the discovery and validation phases, we will utilize pre-formed cohorts of 3,000 cases and 3,000 controls for genetic and genetic epidemiologic studies at MSK, augmented by cases provided by national and international collaborators, including a highly informative subset ascertained by NCI investigators. To inform the discovery of putative urothelial cancer susceptibility genes, we will pursue functional characterization of deleterious genetic mutations identified by the above- mentioned genetic epidemiologic approaches.

项目摘要/摘要 膀胱（尿路上皮）癌症具有大量的遗传成分，估计可遗传 比例约为30％。全基因组协会研究记录了 尿路上皮癌的家族性相对风险类似于家庭膀胱癌注册表 （1.37 vs 1.69）。高度渗透性的癌症易感性基因，例如不匹配中的基因 维修途径（例如，MSH2，MSH6）仅占遗传易感性的一小部分 尿路上皮癌。还有许多关于多盘尿路上皮癌的报道 尚未使用现代测序方法系统地研究的。使用 诱饵捕获对成对的体细胞和种系DNA的下一代测序测定，我们 表明20％的尿路上皮癌患者已知中度至高渗透剂 倾向基因。这些基因中约有70％在DNA损伤响应基因中 途径，易于多种非尿皮癌的基因。初步的 数据还确定了在核苷酸惊喜中的膀胱癌易感性的新型机制 维修途径。该项目旨在通过 来自> 480个亲属的基因分型DNA证明了家庭尿路上皮癌，约有275例患者 早期（≤年龄45岁）和极早（≤30岁）疾病发作，以及选定的子集 尿路上皮癌是多种主要癌症组成部分的1000名患者 一种是尿路上皮癌。我们将利用配对体的下一代测序测定法 和种系DNA，以确定膀胱肿瘤中杂合性的丧失，以及 来自家庭和早期发作病例的种系基因组和外部，以发现假定的膀胱 癌症易感性基因。我们将评估可能有助于神父的候选基因 上述同类研究中的尿路上皮癌，在控制DNA的途径中的基因 修复和在先前全基因组关联研究中鉴定的基因。对于两个发现 和验证阶段，我们将利用3,000例病例和3,000个对照的预成型队列 MSK的遗传和遗传流行病学研究，由国家提供的病例增强 和国际合作者，包括NCI的高度信息子集 调查人员。为了告知发现推定的尿路上皮癌易感性基因，我们将 追求有害基因突变的功能表征 提到的遗传流行病学方法。