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This research investigates how genetic ancestry influences tumor alterations and socioeconomic factors in colorectal cancer patients.

May 7, 2026Open Access

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

Key Points

This research investigates how genetic ancestry influences tumor alterations and socioeconomic factors in colorectal cancer patients.
Analyzed tumor and matched normal whole-exome sequencing data from 16,388 stage I-IV colorectal cancer patients.
Assessed genetic ancestry using supervised local ancestry inference across diverse groups.
Examined the Distressed Community Index to evaluate socioeconomic influences.
80.8% of tumors exhibited microsatellite instability, notably higher in European ancestry compared to African, American, and East Asian ancestries.
Significant differences in driver mutations (APC, BRAF, KRAS, TP53, PIK3CA) between European and other ancestry groups.
DCI scores indicated higher socioeconomic distress in African and American ancestries, although mutation frequencies did not vary with DCI.

Abstract

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. IMPACT: 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.

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