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

肺癌 DNA 损伤修复 (DDR) 通路基因中临床上可操作的种系突变的发现和表征

• 批准号: 10446511
• 负责人: Semanti Mukherjee
• 金额: $ 71.97万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446511
• 关键词: Address; Affect; Age; Algorithms; American; Architecture; BRCA2 gene; Biological; Biological Assay; CHEK2 gene; Cancer Etiology; Cancer Patient; Cancer-Predisposing Gene; Cell Line; Cessation of life; Characteristics; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; DNA Repair; Data; Defect; Diagnosis; Disease; Disease-Free Survival; ERCC2 gene; Early Diagnosis; England; Environmental Risk Factor; Etiology; Excision; Family; Family history of; Family member; Genes; Genetic; Genetic Risk; Genomics; Genotype; Germ-Line Mutation; Goals; Guidelines; High-Risk Cancer; Histologic; Individual; Inheritance Patterns; Inherited; Institution; International; Laboratories; Life; Loss of Heterozygosity; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Medical Genetics; Memorial Sloan-Kettering Cancer Center; Modeling; Modification; Mutation; Newly Diagnosed; Normal tissue morphology; Odds Ratio; Operative Surgical Procedures; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Penetrance; Phenotype; Population Database; Predisposition; Preventive; Primary Neoplasm; Prognostic Marker; Recording of previous events; Recurrence; Research; Risk; Risk Estimate; Risk Factors; Role; Sampling; Smoker; Smoking; Smoking Behavior; Smoking Status; Somatic Mutation; Squamous Cell Lung Carcinoma; Survival Rate; Syndrome; TP53 gene; Technology; Testing; The Cancer Genome Atlas; Tissue Sample; Tobacco; Tobacco smoking behavior; Variant; Vision; Work; base; brca gene; cancer diagnosis; cancer predisposition; cancer risk; cancer type; case control; chemotherapy; cigarette smoking; clinical sequencing; clinically actionable; clinically significant; cohort; computed tomography screening; driver mutation; early onset; exome; exome sequencing; gene repair; genetic linkage analysis; genetic testing; genome sequencing; genome wide association study; genotoxicity; high risk; improved; individual variation; inhibitor; lung cancer screening; malignant breast neoplasm; medical schools; mutational status; never smoker; next generation sequencing; novel; patient derived xenograft model; repaired; targeted treatment; therapeutic evaluation; treatment response; tumor; variant of unknown significance; whole genome

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.

项目概要/摘要 肺癌是全球癌症相关死亡的主要原因，其 5 年生存率为 15%。 一小部分（16%）肺癌病例是在早期诊断出来的，此时更有可能 可以治愈，因此我们需要改进策略来识别高危人群进行强化监测。 吸烟和其他环境因素是肺癌的风险因素，据估计，10-25%的肺癌患者 癌症发生在从不吸烟的人身上，凸显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发现很少有肺癌易感因素 基因，只能解释所有肺癌遗传风险的 14％，因此，肺癌的大部分遗传风险。 随着下一代测序技术的出现，癌症仍然无法解释。 有证据表明DNA损伤修复（DDR）基因中致病性种系突变的贡献 肺癌易感性和病因。我们的初步数据显示，约6.8%的肺癌患者患有肺癌。 DDR 基因中存在致病突变，包括 ATM 中的高和中度渗透突变， 我们发现 DDR 基因中的遗传变异可能是 BRCA2、CHEK2、ERCC2、NBN 和 TP53。 改变肺癌的内在和外在（吸烟或环境）危险因素。 我们提出的研究的目的是确定肺部 DDR 基因遗传突变的临床意义 癌症，研究种系体细胞突变结构和功能特征之间的相互作用 他们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、外显率（风险）修正和临床来进行管理 对于拟议的研究，我们将利用正在进行的 MSK-IMPACT 的结果。 倡议，一个机构范围内的努力，使用配对的肿瘤-正常组织样本进行基因组测试 对 10,000 名肺癌患者进行研究，并对选定的 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 在目标 1 中，我们将发现 DDR 的种系突变。 基因使用新颖的分析框架，通过整合种系体细胞数据进行变异解释。 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 联盟和英国基因组公司在病例对照中确定与肺癌相关的风险 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 基因编辑方法研究种系突变的重要性，并生成患者 从携带 DDR 基因种系突变的患者中衍生出异种移植 (PDX) 模型，以测试 治疗选择；这将为肺癌的研究和治疗选择开辟新的范式 为肺癌患者及其家庭成员提供早期检测指南（级联检测）。