AS591 - Genomic Characterization of Lung Cancer in Female Never-Smokers

Investigator Names and Contact Information

Alice Berger (ahberger@fredhutch.org)

Introduction/Intent

Clinical management of lung cancer, particularly lung adenocarcinoma, has been transformed by the recent discovery of targetable somatic alterations in genes including EGFR, ALK, and MET. However, to date, the majority of lung cancer genomic characterization has been performed on tumors from patients with prior smoking history. We hypothesize that the mechanism of cancer development may be different in never-smokers and smokers, and that characterization of somatic genetic alterations in lung tumors from never-smokers may identify new opportunities for cancer early detection and treatment in this population. We propose to use genome sequencing to identify mechanisms of lung tumorigenesis in women who participated in the Women's Health Initiative study and developed lung cancer during the study. Aim 1 is to identify the somatic genome alterations present in lung adenocarcinomas from never-smokers using whole-exome sequencing. Aim 2 is to apply statistical methods to determine the significantly recurrently mutated genes and copy number alterations. Aim 3 is to describe mutational signatures associated with lung cancer in never-smokers. Because smoking imparts a characteristic transversion-high mutational signature, the presence or absence of this signature in sequencing data from these tumors will suggest whether passive cigarette smoke does or does not contribute to lung cancer in never-smokers. We aim to sequence 130 paired samples of tumor and  blood-derived DNA used as a matched germline control to identify somatic alterations (mutations, copy number changes). 80-90% of the tumor samples will be from never-smokers and 10-20% of samples will be from heavy smokers, for comparative purposes. A minimum of 200 ng of DNA is required; 500 ng is preferred. Samples will be processed with a custom exome capture kit and sequenced on Illumina HiSeq 2500 sequencers at the Dana-Farber Cancer Institute Center for Cancer Genome Discovery. Bioinformatics and statistical analyses will be performed at Fred Hutchinson Cancer Research Center. The completion of this project would yield the largest genome-wide study of somatic mutations in lung cancer from never-smokers to date and may identify actionable somatic alterations that can be targeted for therapy to improve outcomes in women with lung cancer.

We propose to leverage a unique opportunity presented by data and samples collected by the Women's Health Initiative (WHI). The WHI was initially conceived as three overlapping clinical trials and an observational study designed for evaluating the effects of hormone replacement therapy, calcium and vitamin D intake, and diet on cancer and cardiovascular disease risk [2]. Between 1993 and 1998, the WHI enrolled 161,808 post-menopausal women, and over 77,000 remain in active follow-up at present. To date, 3610 lung cancer cases have been reported, resulting in 2910 deaths -- twice as many as deaths due to breast cancer during the same period. 583 cases of lung cancer were diagnosed in women who have never smoked (defined as lifetime consumption of <100 cigarettes). Tumor tissue is currently being collected from WHI cases under the Life and Longevity After Cancer (LILAC) study (mPIs: Garnet Anderson, Bette Caan, Electra Paskett). We propose to determine the somatic genetic alterations in tumor tissue from 130 adenocarcinomas of the lung among the WHI participants, including approximately 110 tumors from never-smokers and 20 heavy smokers, with the following specific aims:

1. To identify the somatic genome alterations present in lung cancers from never-smokers using exome sequencing.
2. To determine the significantly recurrently mutated genes and copy number alterations in lung cancers from never-smokers.
   
3. To describe mutational signatures associated with lung cancer in never-smokers.

The completion of this project would yield the largest study of somatic mutations in lung cancer from never-smokers to date.