A24 The Genome-Wide Mutational Landscape of Lung Cancer in Never-Smokers: The Women’s Health Initiative (WHI) Cohort

Abstract

Lung cancer is the leading cause of cancer deaths worldwide, and a positive history of smoking remains one of the most significant risk factors for lung cancer development. However, about 20% of lung cancer diagnoses are reported in individuals with no smoking history. Lung cancer in never-smokers (LCNS) is clinically distinct from tobacco-induced lung cancer, with a greater proportion of LCNS occurring in women and having adenocarcinoma histology. One of the key challenges in identifying the cancer-promoting genetic events that drive LCNS is the relatively small number of tumors that have been sequenced using genome- or exome-wide approaches. We address this gap through the collection and exome sequencing of lung tumor tissue and matched blood-derived normal DNA from 77 women who participated in the Women’s Health Initiative (WHI), the majority of whom have light or no smoking history. Samples were sequenced with a custom exome approach at the Center for Cancer Genome Discovery (CCGD), Dana-Farber Cancer Institute, with baits for all protein coding regions of the genome and noncoding regions that are frequently rearranged/translocated in lung cancer, such as introns within the ALK gene. Somatic mutations were identified using MuTect2 and mutational significance was determined using MutSig2CV. Preliminary analysis involving 18 tumor/normal pairs identified an enrichment of somatic alterations in genes such as EGFR and TP53. Additionally, tumor purity and copy number alterations were estimated using ichorCNA. Translocation analysis was performed using BreaKmer identifying a CD74-ROS1 fusion. 72% of the cases harbored previously known oncogenic drivers of lung adenocarcinoma such as mutations in EGFR, KRAS, RIT1, and MET with mutations that are clinically targetable using FDA-approved or investigational agents. Overall this project will double the number of exome profiles from never-smokers and, importantly, leverage the extensive metadata curated under the WHI to evaluate secondary/environmental factors such as second-hand smoke and radon exposure and their potential role in LCNS.