The landscape of genomic and socioeconomic variables in colorectal cancer patients based on genetic ancestry.

Despite differences in tumor alterations across genetic ancestries, investigations of the colorectal cancer (CRC) molecular landscape have used self-reported ethnicity instead of genetic ancestry. We used tumor and matched normal whole-exome sequencing data from 16,388 stage I-IV CRC patients to investigate CRC's germline and somatic molecular landscape and the potential influence of socioeconomic factors (Distressed Community Index, DCI) across diverse genetic ancestries. Genetic ancestry determined via supervised local ancestry inference included African (AFR, N=1697), Native American (AMR, N=1291), East Asian (EAS, N=2247), European (EUR, N=9726), Levantine Middle Eastern (LME, N=1192), and South Asian (SAS, N=184). Microsatellite instability was the most common form of hypermutation (80.8%), higher in EUR compared to AFR, AMR, and EAS. Among germline findings, positive results were most common in high-penetrance genes associated with Lynch syndrome. Enrichment patterns included MLH1 (SAS) and PMS2 (AFR). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between the EUR and other ancestry groups in both MSI and MSS tumors. Mutational signatures suggested enrichment of reactive oxygen species and POLE in AFR, colibactin in EAS, and aflatoxin and NTHL1 in SAS. DCI scores differed by ancestry (higher distress in AFR/AMR than in EUR), but driver mutation frequencies did not vary across DCI quintiles. Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. These findings suggest that incorporating ancestry into screening, trials, and precision oncology may improve equity, though outcome-linked prospective studies and implementation research are warranted.