R37CA263320

Discovery and Characterization of Clinically Actionable Germline Mutations in DNA Damage Repair (DDR) Pathway Genes in Lung Cancer - 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. Therefore, improved strategies are needed 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 a few lung cancer predisposing genes, which only explain 14% of all inherited risk for lung cancer. Hence, most of the genetic risk for lung cancer remains unexplained.

With the advent of 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 cancer 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 alterations 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 a 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 a 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 the 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 xenograft (PDX) models from patients carrying germline mutations in DDR genes to test the therapeutic options. This will open a new paradigm of research and treatment options for lung cancer, providing guidelines for lung cancer patients and their family members (cascade testing) for early detection.

Sloan-Kettering Institute For Cancer Research

NOT APPLICABLE

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100656007 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 379% from $719,691 to $3,445,607.