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.

项目摘要/摘要 肺癌是全球与癌症相关死亡的主要原因，5年生存率为15％。仅有的 在早期诊断出肺癌病例的一小部分（16％），当时更有可能是 可以治愈，因此我们需要改进的策略，以确定高风险的个人进行密集监视。虽然 吸烟和其他环境因素是肺癌的风险，据估计有10-25％的肺 癌症发生在永不吸烟者中，突出了遗传因素在肺癌中的潜在作用。 家族性肺癌以及基因组广泛的关联研究已经发现很少有肺癌 基因，仅解释了所有继承肺癌风险的14％。因此，肺的大部分遗传风险 癌症仍然无法解释。随着下一代测序技术的出现，新兴 证据表明，致病性系突变在DNA损伤修复（DDR）基因中的贡献 肺癌的易感性和病因。我们的初步数据表明，约6.8％的肺癌患者 在DDR基因中具有病原突变，包括ATM中的高和中等渗透突变， BRCA2，CHEK2，ERCC2，NBN和TP53。我们假设DDR基因中的遗传选择可能 修改肺癌的内在和外在（烟草吸烟或环境）危险因素。目标 我们提出的研究是确定肺中DDR基因中遗传突变的临床意义 癌症，研究种系 - 及其性突变体系结构之间的相互作用，并在功能上表征 他们了解肺癌易感性的机制。我们的发现将为临床和预防性提供信息 通过阐明基因型 - 表型相关性，渗透率（风险）修改和临床管理 一般定义的同类群体中的结果。对于拟议的研究，我们将利用正在进行的MSK影响力 倡议，这是一种使用成对肿瘤 - 正常组织样品进行基因组测试的机构范围的努力 在10,000例肺癌和整个外显子体测序中，用于选定的400个肺癌 患有任何癌症家族史或早期诊断的患者（诊断年龄<50岁） 或多个原发性肿瘤的个人病史。在AIM 1中，我们将发现DDR中的种系突变 通过整合新分析框架的基因，通过整合种系 - 及其用于变异解释的基因。我们 将与国际肺癌合作，在病例控制队列中复制我们的发现 联盟和英国基因组学英国，并确定病例控制中与肺癌相​​关的风险 队列和家庭继承模式（AIM 2）。我们将建立临床和功能 使用CRISPR基因编辑方法的种系突变的重要性，并产生患者 来自DDR基因中携带种系突变的患者的衍生Xenograph（PDX）模型，以测试 治疗选择；这将为肺癌的研究和治疗方案开放新的范式 肺癌患者及其家庭成员（级联测试）的指南。