Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles

Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.

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Publication Details

Journal
Cancer Research
Published
2025-03-24
DOI
https://doi.org/10.1158/0008-5472.can-24-0747
Citations
5
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
7.36

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article

Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles

Brooke L. Fridley, Jennifer A. Freedman, Kun Jiang, Teresita Muñoz-Antonia et al.
5 citations
Cancer Research
Genetic factors in colorectal cancer
7.36
article

Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles

Brooke L. Fridley, Jennifer A. Freedman, Kun Jiang, Teresita Muñoz-Antonia, Nicole C. Loroña, Jane C. Figueiredo, Clifton G. Fulmer, Ozlen Saglam, Jason B. Fleming, Kritika Shankar, Julie Dutil, Mariana C. Stern, Jamie K. Teer, W. Douglas Cress, Edna R. Gordián, Erin M. Siegel, Seth Felder, Stephanie L. Schmit, Domenico Coppola, Idhaliz Flores, Hannah J. Hoehn, Julian Sanchez, Jun Gong, José A. Oliveras Torres, Diana B. Díaz, Nathalie T. Nguyen, Marco Matejcic
article en
5 citations

Abstract

Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.

Cancer ResearchVol. 85(10)
University of Southern California (US), Cedars-Sinai Medical Center (US), Cleveland Clinic (US), Children's Mercy Hospital (US), Ponce Health Sciences University (PR), Duke University (US), University of Puerto Rico System (PR), Moffitt Cancer Center (US), Cleveland Clinic Lerner College of Medicine (US), Clinical Research Institute (US), Duke Medical Center (US), The University of Texas Southwestern Medical Center (US)
Pfizer, Moffitt Cancer Center, Exelixis, Incyte, Natera, Eisai, National Institutes of Health, EMD Serono, National Cancer Institute, Janssen Biotech
Good health and well-being
Openalex Percentile: Top 3%
Genetic factors in colorectal cancer
7.36
DOIOpen Access PDFOpenAlex
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