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 EGFR, KRAS, and STK11. A local Native American ancestry risk score was more strongly correlated with EGFR mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in EGFR and KRAS mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association.See related commentary by Gomez et al., p. 534.This article is highlighted in the In This Issue feature, p. 521.

Fig. 1:. Genomic differences in LUAD across patient populations.

A) TMB, SCNA burden and the frequency of KRAS mutations are lower, while the frequency of EGFR mutations is higher, in lung cancers from East Asian patients, compared to lung cancers from patients of European and/or African origin. The somatic EGFR mutation rate in lung cancer varies among Latin American countries. Mexican and Colombian populations have varying degrees of admixed NAT ancestry, as indicated in blue. B) Both germline variations and environmental exposures such as smoking can predispose to somatic alterations driving the development of lung cancers, that may cause the genomic differences across populations.

Fig 2:. Somatic genome analysis of lung cancers from Mexico and Colombia.

Co-mutation plot displays alterations in known activators of the RTK/RAS/RAF pathway, tumor suppressor genes and significantly amplified genes. * indicates that oncogenic mutations in EGFR and KRAS as well as truncating mutations in STK11 are associated with NAT ancestry, but other somatic alterations are not; correlations with mutations are controlled for TMB. LATAM: Latin American. The mutation frequency for EUR LUAD is obtained from the TCGA dataset(51). The mutation frequency for EAS LUAD is obtained from Chen et al 2020(12).

Fig. 3:. Targetable LUAD driver genes associated with genetic ancestry.

A) The percentage of NAT germline ancestry is positively correlated with the percentage of somatic EGFR mutations, and negatively correlated with the percentage of somatic KRAS mutations. Color bar represents the number of samples in the NAT ancestry percentage range. B) Association of targetable LUAD driver genes with NAT ancestry, mutational signature and gender (n=705) (left), and the association in never smokers only (n=387) (right). Multivariable logistic regression P values are shown, with NAT ancestry percentage, gender, smoking and APOBEC signature as covariates. Red dots represent P value <0.05. Lines represent 95% confidence intervals.

Fig 4:. Germline local ancestry in association with somatic EGFR and KRAS mutations.

A) Genome-wide association of local NAT ancestry with EGFR (left) and KRAS (right). “NAT ancestry high” indicates positive association, whereas “NAT ancestry low” indicates negative association. Red line indicates P=0.05. Orange line indicates genome-wide significance threshold (P<5x10⁻⁵). B) Association of local ancestry risk score with somatic EGFR or KRAS mutations, controlling for global ancestry (proportion of overall NAT ancestry).