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.
