Association of Genetic Ancestry With Molecular Tumor Profiles in Colorectal Cancer

Authors

Brooke Rhead
David M Hein
Yannick Pouliot
Justin Guinney
Francisco M De La Vega
Nina N Sanford

Language

English

Publication Date

8-13-2024

Journal

Genome Medicine

DOI

10.1186/s13073-024-01373-w

PMID

39138508

PMCID

PMC11321170

PubMedCentral® Posted Date

8-13-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Background: There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.

Methods: Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily late-stage CRC patients. Genetic ancestry proportions for five continental groups-Africa (AFR), American indigenous (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS)-were estimated using ancestry informative markers. To address data gaps, race and ethnicity categories were imputed, resulting in assignments for 952 Hispanic/Latino, 420 non-Hispanic (NH) Asian, 1061 NH Black, and 5763 NH White individuals. We assessed association of genetic ancestry proportions and imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in 2608 expression profiles, as well as 1957 consensus molecular subtypes (CMS).

Results: Increased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS, and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the NH Black category were associated with higher rates of CMS3, while a higher proportion of Hispanic/Latino patients exhibited indeterminate CMS classifications.

Conclusions: Molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity were identified. The association of AFR ancestry with increased KRAS mutations aligns with higher CMS3 subtype rates in NH Black patients. The increase of indeterminate CMS in Hispanic/Latino patients suggests that subtype classification methods could benefit from enhanced patient diversity.

Keywords

Humans, Colorectal Neoplasms, Mutation, Male, Female, Middle Aged, Proto-Oncogene Proteins B-raf, Aged, Class I Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins p21(ras), Biomarkers, Tumor, Adenomatous Polyposis Coli Protein

Published Open-Access

yes

Recommended Citation

Rhead, Brooke; Hein, David M; Pouliot, Yannick; et al., "Association of Genetic Ancestry With Molecular Tumor Profiles in Colorectal Cancer" (2024). Faculty, Staff and Student Publications. 6615.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6615