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: 10453634
• 负责人: Dean F. Bajorin
• 金额: $ 34.33万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453634
• 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 膀胱癌(尿路上皮癌)是一种重要的遗传性成分，据估计可遗传 约30%的分数。全基因组关联研究记录了一项估计 尿路上皮癌的家族相对风险与家族性膀胱癌登记中的相似 (1.37比1.69)。高穿透性癌症易感基因，如错配中的那些- 修复途径(如MSH2、MSH6)只占遗传易感性的一小部分 尿路上皮癌。也有许多关于多病例尿路上皮癌家族的报道。 尚未使用现代测序方法进行系统研究。vbl.使用 诱饵捕获下一代体细胞和种系DNA的测序分析 研究显示，20%的尿路上皮癌患者已知有中到高度渗透性 易感基因。这些基因中约有70%在DNA损伤反应基因中 通路，即易患广泛的非尿路上皮癌的基因。初步 数据还确定了一种新的核苷酸切除导致膀胱癌易感性的机制 修复途径。该项目旨在通过以下方式确定新的尿路上皮癌易感基因 对480个家族性尿路上皮癌患者进行DNA基因分型，约275名患者 起病早(≤年龄45岁)和极早(≤年龄30岁)，以及部分以上人群 1000例患者，其中尿路上皮癌是多原发癌的组成部分 一种是尿路上皮癌。我们将利用下一代配对体细胞的测序分析 和生殖系DNA来鉴定膀胱肿瘤的杂合性丢失，以及询问 来自家族性和早发性病例的生殖系基因组和外显子基因组发现可能的膀胱 癌症易感基因。我们将评估可能有助于遗传的候选基因 尿路上皮癌在上述亲缘关系研究中，基因控制DNA的途径 修复，以及在先前的全基因组关联研究中确定的基因。对于这两个发现 和验证阶段，我们将利用预先形成的3,000个病例和3,000个对照队列来进行 MSK的遗传和遗传流行病学研究，由National提供的病例加强 和国际合作者，包括NCI确定的高度信息量的子集 调查人员。为了告知可能的尿路上皮癌易感基因的发现，我们将 对上述确定的有害基因突变进行功能表征- 提到了遗传流行病学方法。