Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations

Abstract

AbstractAncestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry.Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression.TP53,APC, andKRASwere the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewerKRAS(OR=0.64, 95%CI=0.41-0.97, p=0.037) andPIK3CAmutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation inKNCN(OR=1.34, 95%CI=1.09–1.66, p=5.74×10-3) andTMEM184B(OR=1.53, 95%CI=1.10–2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status inCDC27(LRT p=0.0084) and betweenSMAD2mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048).Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities.SignificanceOur data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.