Genetic Contribution to Nonsquamous, Non-Small Cell Lung Cancer in Nonsmokers

Abstract

Introduction: Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologic subtypes is unknown.

Methods: A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (N = 5408) was analyzed to evaluate the heritable contribution to lung cancer histologic subtype in smokers (n = 1751) and nonsmokers (n = 818). Statistical methods were used to test for significant excess relatedness of lung cancer cases.

Results: Significant excess distant relatedness was observed for all lung cancer histologic subgroups analyzed except for the SCLC subset (p = 0.213). When histologic subsets of smokers and nonsmokers with lung cancer were considered, excess relatedness was observed only in nonsmokers with NSCLC (n = 653 [p = 0.026]) and, in particular, in those nonsmokers with the nonsquamous histologic subtype (n = 561 [p = 0.036]). A total of 61 pedigrees demonstrating a significant excess risk of nonsquamous lung cancer in nonsmokers were identified, and an excess of cases in females was observed among the individuals with these high-risk pedigrees.

Conclusions: This analysis supports a genetic predisposition to lung cancer carcinogenesis in nonsmokers with nonsquamous NSCLC.

Keywords: Adenocarcinoma; Genetic predisposition; Histologic subtype; Lung cancer; Squamous cell carcinoma; UPDB.