Lung Cancer Research

It is well known that the most significant risk factor for lung cancer is cigarette smoking. However, an estimated 8 percent of men and 20 percent of women with lung cancer are never-smokers. Currently, the causes of lung cancer in non-smokers or never-smokers are not well understood. We are trying to understand whether inherited factors may partly explain the development of lung cancer in patients who did not smoke.

Genetics and Lung Cancer: Our Studies on Lung Cancer

INHERIT

The finding that lung cancers harboring EGFR mutations occur more commonly in never-smokers has added complexity to the current understanding of lung cancer risk and predisposition. The most important risk factor for lung cancer development is clearly a history of smoking; indeed, genome-wide association studies have found that the gene most associated with lung cancer risk may be one that influences nicotine metabolism. Yet risk factors for the development of lung cancer in never-smokers are less clear. As smoking rates decline, lung cancer in never-smokers may come to represent a larger proportion of this deadly disease, necessitating an improved understanding of the risk factors for its development.

Germline EGFR mutations, which have been identified in a handful of cases of familial lung cancer, have the potential to provide insight into EGFR-mutant lung cancer risk and carcinogenesis. However, few families have been identified since germline EGFR mutations were first described in 2005, impairing our ability to study this phenomenon. One study attempted to screen for germline EGFR mutations in peripheral blood specimens from 369 never-smokers with lung cancer, but found only 2 (a prevalence of 0.5%). Interestingly, the best described germline EGFR mutation (T790M) is similarly rare in lung cancer patients at diagnosis. A recent study has found that 5 of 10 patients (50%) with baseline T790M in their lung cancer also carried a germline allele. We therefore hypothesize that identification of EGFR T790M mutations through routine tumor genotyping, now a standard component of lung cancer management, will allow us to identify and study patients at high risk of carrying germline EGFR mutations.

The INHERIT study is being led by researchers at the Dana-Farber Cancer Institute. The purpose of the INHERIT study is to perform germline testing of patients with lung cancers carrying T790M mutations, and thus at risk of carrying a germline T790M mutations. This will first allow us to prospectively study the prevalence of germline T790M mutations in patients with T790M-mutant lung cancer. Those patients found to carry germline T790M mutations will receive genetic counseling, and will be asked to invite their family members to participate in the study as well. All participants found to carry germline T790M will submit a chest CT scan (either archived or prospectively obtained) for characterization of lung nodules in these families. This study will be facilitated by the Addario Lung Cancer Medical Institute (ALCMI), a patient-founded non-profit research consortium which will coordinate tissue banking and analysis, CT scan collection, and clinical data collection.