Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations

Abstract

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in <i>EGFR, KRAS</i>, and <i>STK11</i>. A local Native American ancestry risk score was more strongly correlated with <i>EGFR</i> mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic <i>EGFR</i> and <i>KRAS</i> mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in <i>EGFR</i> and <i>KRAS</i> mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association.<i>See related commentary by Gomez et al., p. 534</i>.<i>This article is highlighted in the In This Issue feature, p. 521</i>.