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

项目总结/摘要 膀胱（尿路上皮）癌有很大的遗传成分，估计遗传 分数约为30%。全基因组关联研究记录了 尿路上皮癌的家族性相对危险度与家族性膀胱癌登记中所见相似 (1.37对比1.69）。高度渗透的癌症易感基因，如那些在错配- 修复途径（如，MSH 2，MSH 6）仅占遗传易感性的一小部分， 尿路上皮癌。也有许多报告多例尿路上皮癌激酶 这些基因还没有被现代测序方法系统地研究过。使用 诱饵捕获配对体细胞和生殖系DNA的下一代测序测定，我们 显示20%的尿路上皮癌患者具有已知的中度至高度渗透剂， 易感基因这些基因中约70%属于DNA损伤反应基因 途径，基因，易患广谱的非尿路上皮癌。初步 数据还确定了一种新的膀胱癌易感性机制， 修复途径该项目旨在通过以下方法鉴定新的尿路上皮癌易感基因： 基因分型DNA来自>480例家族性尿路上皮癌，约275例患者， 早期（≤ 45岁）和极早期（≤ 30岁）疾病发作， 1000例尿路上皮癌是多种原发性癌症的组成部分的患者， 一个是尿路上皮癌。我们将利用下一代的配对体细胞测序分析， 和生殖系DNA来鉴定膀胱肿瘤中的杂合性缺失，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组，以发现推定的膀胱癌 癌症易感基因我们将评估可能导致遗传性疾病的候选基因， 尿路上皮癌在上述同类研究中，基因在控制DNA的途径中， 修复，以及在先前的全基因组关联研究中鉴定的基因。因为这个发现 和验证阶段，我们将利用预先形成的3,000例病例和3,000例对照队列， MSK的遗传和遗传流行病学研究，由国家 和国际合作者，包括NCI确定的信息量丰富的子集 investigators.为了告知推定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。

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.