Abstract：
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 KRASG12C 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 KRASG12D. 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.
摘要：
KRAS突变是非小细胞肺癌（NSCLC）患者中最常见的致癌驱动因素。然而,详细了解自我报告的种族和/或种族（SIRE），基因推断祖先（GIA），它们的相互作用对KRAS突变的影响在很大程度上是未知的。这里,我们调查了SIRE,定量GIA,来自波士顿肺癌生存队列和中国OrigiMed队列的3918例多种族队列中的KRAS突变及其等位基因特异性亚型，以及1450例NSCLC患者的独立验证队列。这个全面的分析包括详细的协变量，包括诊断时的年龄，性别,临床分期,癌症组织学,和吸烟状况。我们报道SIRE与KRAS突变显著相关,按性别修改，SIRE-亚洲患者的KRAS突变率较低，transversion替换,和等位基因特异性亚型KRASG12C与SIRE-White患者相比，在调整了潜在的混杂因素后。此外，发现GIA与KRAS突变相关，欧洲血统比例较高的患者患KRAS突变的风险增加，特别是更多的过渡替换和KRASG12D。值得注意的是,在SIRE-白人患者中，欧洲血统的增加与KRAS突变的可能性更高有关，而混合美国血统的增加与可能性的降低有关，这表明定量GIA提供了SIRE以外的其他信息。SIRE协会,GIA,它们与NSCLC中KRAS驱动突变的相互作用突出了将两者纳入基于人群的癌症研究的重要性，旨在完善临床决策过程并减轻健康差异。
