Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer.

The KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, a detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3,918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1,450 patients with NSCLC. This comprehensive analysis included detailed covariates such as age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRAS^G12C compared to SIRE-White patients after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRAS^G12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.