Abstract 2151: Additional impact of genetic ancestry over self-reported race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer

Abstract Background: KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, the interplay between self-reported race and/or ethnicity (SIRE) and genetically inferred ancestry (GIA) on KRAS mutations and allele-specific subtypes is largely unknown. Methods: A total of 3918 NSCLC patients from the Chinese OrigiMed (OM) cohort (n=2039) and Boston Lung Cancer Survival (BLCS) cohort (n=1879) were included, all of whom had baseline covariates including age, sex, clinical stage, SIRE, histology and smoking status. KRAS mutation and subtypes were determined by targeted NGS panels in each cohort, and KRAS mutation outcomes, including KRAS mutation, KRAS subtypes, and KRAS transversion and transition were analyzed. GIA was inferred from paired germline data for patients in the BLCS cohort. Multivariable and multinomial logistic regressions were employed to assess the associations between SIRE, GIA and KRAS outcomes. Results: In the entire cohort, 804 (20. 5%) patients harbored KRAS mutation, with a considerably higher prevalence of 31. 5% observed in BLCS compared to 10. 4% in OM cohort. Patients with self-identified Asian was associated with a significantly lower rate of KRAS mutation (OR = 0. 44, 95% CI: 0. 22 - 0. 81, P = 0. 01), transversion substitutions (OR = 0. 24, 95% CI: 0. 10 - 0. 62, P = 0. 003) and KRASG12C (OR = 0. 17, 95% CI: 0. 04 - 0. 72, P = 0. 02) compared to SIRE-White patients after adjusting for confounders including smoking status, sex and histology. The association of SIRE and KRAS driver mutation was further modified by sex, with Asian women demonstrating lower risk compared to Asian men, while the opposite trend was observed in SIRE-White patients. Increased European ancestry was associated with a higher risk of KRAS mutation (OR per 10% increase = 1. 05, 95% CI: 1. 00 - 1. 09, P = 0. 03), particularly with more transition substitutions (OR per 10% increase = 1. 10, 95% CI: 1. 01 - 1. 21, P = 0. 03) and KRASG12D (OR per 10% increase = 1. 18, 95% CI: 1. 04 - 1. 34, P = 0. 01). This association was even more pronounced in patients of increased Northern European ancestry. Furthermore, even among SIRE-White patients, a 10% increase in European ancestry was associated with an additional 6% increase in the likelihood of KRAS mutations (OR = 1. 06, 95% CI: 1. 01 - 1. 12, P = 0. 03), while a 10% increase in Admixed American ancestry was associated with a 6% decreased likelihood of KRAS mutations (OR = 0. 94, 95% CI: 0. 88 - 0. 99, P = 0. 04). Results were validated in an independent cohort of 1450 patients. Conclusion: Self-reported race/ethnicity and genetic ancestry are both associated with KRAS driver mutations and allele-specific subtypes of NSCLC. This work highlights the significance of integrating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities. Citation Format: Xinan Wang, Kangcheng Hou, Biagio Ricciuti, Joao V. Alessi, Xihao Li, Federica Pecci, Rounak Dey, Jia Luo, Mark M. Awad, Alexander Gusev, Xihong Lin, Bruce E. Johnson, David C. Christiani. Additional impact of genetic ancestry over self-reported race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2151.