Identifying germline risk mutations for early-onset and familial NSCLC

2014

Early Detection Research Award

Zeynep H. Gümüş, PhD

Icahn School of Medicine at Mount Sinai

New York

Steven M. Lipkin, MD, PhD

Joan & Sanford I. Weill Medical College of Cornell University

New York

Kenneth Offit, MD, MPH

Memorial Sloan Kettering Cancer Center

New York

Each year, more than 22,000 people who have never smoked are diagnosed with lung cancer, many at younger ages. Dr. Gümüş and team will identify underlying genes that could indicate a higher risk of developing lung cancer, similar to what has been found with certain forms of breast, colorectal, and pancreatic cancers. People who carry the high-risk genes could then be monitored more carefully.

Research Summary

Lung cancer is the leading cause of cancer death in the United States. Early stage disease can be treated surgically with good outcomes; however, most patients are diagnosed at a later stage when potentially curative surgery is no longer possible. We clearly need improved strategies for early stage lung cancer detection. An important gap in these efforts is identifying persons at high risk. Some patients have a family history of the disease or are affected at a young age with no history of smoking. Indeed, lung cancer has been diagnosed in children as young as eleven. These findings are similar to those seen for breast and ovarian cancers in BRCA mutation carriers like Angelina Jolie; they suggest that genetics also play an important role in lung cancer risk. The overall goal of this project is to identify genes that, when mutated, increase the risk of developing lung cancer. This team has successfully discovered mutations in several genes that cause, respectively, hereditary breast, colon and pancreatic cancers or leukemias. They propose a similar approach for lung cancer patients who have never smoked to identify gene mutations that predispose them to the disease. By using genetics to identify high-risk patients, the team can focus efforts on frequent screening and, potentially, chemoprevention. As smoking is a primary disease risk factor, smokers with these mutations will also benefit from cessation efforts. Frequent surveillance of high-risk individuals will enable the early detection of cancer before it spreads; this can help improve patients’ chances of beating the disease entirely.

Technical Abstract

Prognosis for non-small cell lung cancer (NSCLC) is substantially better in early-stage as opposed to late-stage disease. If high-risk individuals could be effectively identified, they could significantly benefit from intensive surveillance, early detection, and prevention strategies. While smoking is a primary risk factor, only about 15% of smokers develop the disease. Consistent with a genetic predisposition, some patients have a family history of the disease and are affected at a young age, although they have never smoked. Unfortunately, NSCLC predisposing gene mutations are poorly characterized. We aim to identify novel NSCLC germline risk gene mutations. Our team members have previously identified novel risk gene mutations for several familial cancers. We have assembled a large clinically and molecularly well-characterized NSCLC case-control cohort of never-smokers, performed whole-exome sequencing (WES) on familial and early onset NSCLC probands, identified promising candidate risk genes, and externally validated selected samples. We follow a resource-conscious approach by focusing on a founder population, Ashkenazi Jews (AJ), to decrease genetic heterogeneity and to increase the allele frequencies of candidate recurrent risk mutations. We will perform WES on additional familial and early onset NSCLC probands to identify recurrently mutated NSCLC genes and cross-validate the genes using whole-genome sequencing on matching tumors. The gene candidates identified will be validated using a targeted sequencing approach in a larger non-AJ cohort. These are anticipated to provide new biological insights, serve as future chemoprevention targets, and be used in the development of a genetic diagnostic test to identify high-risk individuals.

Key words

Adenocarcinoma

Early detection

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Risk profile

Stage 0

Stage I

Identifying germline risk mutations for early-onset and familial NSCLC

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