Abstract Lung cancer remains the leading cause of cancer-related death worldwide, killing more than 1.8 million people each year. A key unresolved question about lung cancer is the relationship between patient ancestry, sex, and somatic mutations in epidermal growth factor receptor (EGFR). In lung adenocarcinoma, EGFR mutations are significantly more common patients of East Asian descent (∼50%) than in patients of European or African descent (∼10%), as well as in women and non-smokers. To explore the underlying factors contributing to these disparities, we performed an analysis of lung cancer genomes from diverse ancestries using data from Foundation Medicine (n = 64,052) and GENIE (n = 21,215). We found that the frequency of in-frame deletions in Exon 19 and point mutations at L858R – together accounting for 90% of EGFR mutations – varied significantly and independently by patient ancestry and sex. Specifically, patients of African and South Asian ancestry with EGFR mutations were twice as likely to harbor Exon 19 deletions compared to those of European ancestry. In contrast, L858R mutations were independently enriched in patients of East Asian ancestry, in women, and in patients with cooccurring RBM10 loss-of-function mutations. RBM10, an X-linked splicing factor, exhibited a higher mutant allele frequency was more likely to cooccur with EGFR L858R mutations in East Asians than in other groups, even after controlling for patient age and sex, implicating this gene in observed disparities in lung cancer mutations. These findings strongly suggest the presence of a sex-modulated germline risk factor influencing EGFR mutation risk in lung across ancestries, highlighting a novel interaction between RBM10 and EGFR mutations. Citation Format: Anders B. Dohlman, Ethan Shurberg, Meagan Montesion, Smruthy Sivakumar, Owen Hirschi, Alaina Shumate, Garrett Frampton, Alexander Gusev, Matthew Meyerson. An EGFR hotspot mutation interacts with RBM10 to influence lung cancer risk in East Asians abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr B146.
Dohlman et al. (Thu,) studied this question.