Discovery and characterization of clinically actionable germline mutations in DNA damage repair (DDR) pathway genes in lung cancer

项目总结/摘要 肺癌是全球癌症相关死亡的主要原因，5年生存率为15%。只 一小部分（16%）肺癌病例在早期被诊断出来， 因此，我们需要改进战略，以确定高风险个人进行密集监测。虽然 吸烟和其他环境因素是肺癌的危险因素，据估计，10-25%的肺癌患者 癌症发生在从不吸烟者身上，突出了遗传因素在肺癌中的潜在作用。 家族性肺癌以及全基因组关联研究已经确定了很少的肺癌易感因素， 基因，这只能解释14%的肺癌遗传风险。因此，大多数肺癌的遗传风险 癌症仍然无法解释。随着新一代测序技术的出现， 有证据表明，DNA损伤修复（DDR）基因中的致病性生殖系突变在 肺癌的易感性和病因。我们的初步数据显示，约6.8%的肺癌患者 在DDR基因中携带致病性突变，包括ATM中的高度和中度渗透突变， BRCA 2、CHEK 2、ERCC 2、NBN和TP 53。我们假设DDR基因的遗传变异可能 改变肺癌的内在和外在（吸烟或环境）风险因素。目标 我们提出的研究的目的是确定肺DDR基因遗传突变的临床意义， 癌症，研究生殖细胞-体细胞突变结构和功能特征之间的相互作用 了解肺癌易感性的机制。我们的研究结果将为临床和预防提供信息， 通过阐明基因型-表型相关性、突变率（风险）修改和临床 在基因定义的队列中的结果。对于拟议的研究，我们将利用正在进行的MSK-IMPACT 这是一项全机构范围内的努力，使用配对的肿瘤正常组织样本进行基因组检测 在10，000名肺癌患者中，以及对选定的400名肺癌患者进行全外显子组测序， 有任何癌症家族史或早期诊断（诊断时年龄<50岁）的患者 或多个原发性肿瘤的个人病史。在目标1中，我们将发现DDR中的种系突变， 基因使用新的分析框架，通过整合种系体细胞数据的变异解释。我们 我将与国际肺癌组织合作，在病例对照队列中复制我们的发现。 联合会和英国基因组学英国和确定风险与肺癌的病例对照 队列和家庭遗传模式（目标2）。我们将建立临床和功能 使用CRISPR基因编辑方法研究生殖系突变的重要性，并产生患者- 来自携带DDR基因生殖系突变的患者的衍生异种移植（PDX）模型，以测试 治疗选择;这将打开肺癌研究和治疗选择的新范式 肺癌患者及其家庭成员（级联检测）的早期检测指南。

Project Summary/Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, with a 5-year survival rate of 15%. Only a small proportion (16%) of lung cancer cases are diagnosed at an early stage, when it is more likely to be curable, thus we need improved strategies to identify high-risk individuals for intensive surveillance. Although cigarette smoking and other environmental factors are risks for lung cancer, it is estimated that 10-25% of lung cancers occur in never-smokers, highlighting the potential role of inherited genetic factors in lung cancer. Familial lung cancer as well as genome wide association studies have identified few lung cancer predisposing genes, which only explains 14% of all inherited risk for lung cancer. Hence, most of the genetic risk for lung cancer remains unexplained. With the adven t of the next-generation sequencing technologies, emerging evidence suggests the contribution of pathogenic germline mutations in DNA damage repair (DDR) genes in lung cancer susceptibility and etiology. Our preliminary data shows that about 6.8% of lung can cer patients harbored pathogenic mutations in DDR genes including high and moderate penetrant mutations in ATM, BRCA2, CHEK2, ERCC2, NBN and TP53. We hypothesize that the genetic alternations in DDR genes may modify the intrinsic and extrinsic (tobacco smoking or environmental) risk factors of lung cancer. The objectives of our proposed study are to determine the clinical significance of inherited mutations in DDR genes in lung cancer, study the interplay between germline-somatic mutational architecture and functionally characterize them to understand the mechanism of lung cancer susceptibility. Our findings will inform clinical and preventive management by elucidating genotype-phenotype correlations, penetrance (risk) modification, and clinical outcomes in genetically defined cohorts. For the proposed study, we will leverage the ongoing MSK-IMPACT initiative, an institution-wide effort to perform genomic testing using paired tumor–normal tissue samples in 10,000 patients with lung cancers as well as whole exome sequencing for a selected 400 lung cancer patients who had either family history of any cancer, or early diagnosis (age at diagnosis <50 years) or personal history of multiple primary tumors. In aim 1, we will discover germline mutations in DDR genes using novel analytical framework by integrating germline-somatic data for variant interpretation. We will replicate our findings in a case-control cohort in collaboration with the International Lung Cancer Consortium and England Genomics UK and determine risk associated with lung cancer in a case-control cohort and the pattern of inheritance in families (Aim 2). We will establish the clinical and functional significance of the germline mutations using the CRISPR gene editing approach and generate patient- derived xenograph (PDX) models from patients carrying germline mutations in DDR genes to test the therapeutic options; this will open the new paradigm of research and treatment options for lung cancer guidelines for lung cancer patients and their family members (cascade testing) for early detection.