Association of germline variants with KRAS-mutation status in colorectal cancer

Somatic mutations in KRAS are a common driver of colorectal cancer (CRC) and present at different frequencies by race, sex, tumor site, ethnicity, and genetic similarity. Inherited germline variants may influence tumor somatic mutation frequency by altering mutation or DNA repair processes or altering cellular, immunological and/or microenvironmental responses after a mutation. We hypothesized that the germline genetic background modifies somatic KRAS mutation frequency in CRC. To test this, we performed a genome-wide association study (GWAS) in 7071 individuals with CRC, using KRAS mutation status as the phenotype. Single-nucleotide variants were chosen for validation analyses based on P values from the discovery GWAS, predicted in silico functional effects, and proximity to genes with potential cancer relevance. A validation analysis of 101 SNVs of interest was performed in 2482 individuals. No SNVs were significantly associated with KRAS-mutant CRC (P value < 0.0005). One variant rs73067863-T showed a non-significant exploratory association with fewer KRAS-mutant tumors in the combined sample (P value = 9.7 × 10<sup>-7</sup>, OR = 0.75). Follow-up studies are needed to determine if these or other germline variants impact population differences in KRAS mutations in CRC.

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Journal
Scientific Reports
Published
2026-02-13
DOI
https://doi.org/10.1038/s41598-026-39644-8
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Association of germline variants with KRAS-mutation status in colorectal cancer

Schoen Re, Tanish Gandhi, Johnny R. Ramroop, Cara Dauch et al.
Scientific Reports
Genetic factors in colorectal cancer
article

Association of germline variants with KRAS-mutation status in colorectal cancer

Schoen Re, Tanish Gandhi, Johnny R. Ramroop, Cara Dauch, Nicole C. Loroña, Bethany Van Guelpen, Christina C. Newton, Claire Elizabeth Thomas, Andrew J. Pellatt, Robert S. Steinfelder, Jonathan Andrew Nowak, Meredith A.J. Hullar, Amanda M. Bloomer, Quang M. Trinh, Patrick Stevens, Elom K. Aglago, Peter Georgeson, Amy J. French, Nijole P. Tjader, Owen Meadows, Heather L. Hampel, Rachel Pearlman, Joseph P. McElroy, Iona Cheng, Jennifer B. Permuth, Caroline Y. Um, Niki Dimou, Wen-Yi Huang, Wei Sun, Anita R. Peoples, Maria F. Gomez, Erin M. Siegel, Syed H. Zaidi, Graham G. Giles, Amanda Ewart Toland, Stephen B. Gruber, Jane Figueiredo, Daniel D. Buchanan, Yin Cao, Mireia Obón-Santacana, Sonja I. Berndt, Peter T. Campbell, Ulrike Peters, Stephanie L. Schmit, Victor Moreno, David A. Drew, Konstantinos Tsilidis, Andrew T. Chan, Michael Hoffmeister, Amanda I. Phipps, Tomotaka Ugai, Marios Giannakis, Hermann Brenner, Jeroen R. Huyghe
article en

Abstract

Somatic mutations in KRAS are a common driver of colorectal cancer (CRC) and present at different frequencies by race, sex, tumor site, ethnicity, and genetic similarity. Inherited germline variants may influence tumor somatic mutation frequency by altering mutation or DNA repair processes or altering cellular, immunological and/or microenvironmental responses after a mutation. We hypothesized that the germline genetic background modifies somatic KRAS mutation frequency in CRC. To test this, we performed a genome-wide association study (GWAS) in 7071 individuals with CRC, using KRAS mutation status as the phenotype. Single-nucleotide variants were chosen for validation analyses based on P values from the discovery GWAS, predicted in silico functional effects, and proximity to genes with potential cancer relevance. A validation analysis of 101 SNVs of interest was performed in 2482 individuals. No SNVs were significantly associated with KRAS-mutant CRC (P value < 0.0005). One variant rs73067863-T showed a non-significant exploratory association with fewer KRAS-mutant tumors in the combined sample (P value = 9.7 × 10<sup>-7</sup>, OR = 0.75). Follow-up studies are needed to determine if these or other germline variants impact population differences in KRAS mutations in CRC.

Scientific ReportsVol. 16(1)
Broad Institute (US), Ontario Institute for Cancer Research (CA), University of Southern California (US), City College of New York (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), American Cancer Society (US), National Institutes of Health (US), Barnes-Jewish Hospital (US), Albert Einstein College of Medicine (US), City Of Hope National Medical Center (US), Cleveland Clinic (US), The Royal Melbourne Hospital (AU), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), The University of Melbourne (AU), City University of New York (US), German Cancer Research Center (DE), University of California, San Francisco (US), University of Ioannina (GR), Cancer Council Victoria (AU), University of Washington (US), Washington University in St. Louis (US), Heidelberg University (DE), The Ohio State University Wexner Medical Center (US), Moffitt Cancer Center (US), Cleveland Clinic Lerner College of Medicine (US), Institut d'Investigació Biomédica de Bellvitge (ES), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Jewish Hospital (US), Institut Català d'Oncologia (ES), Dana-Farber Cancer Institute (US), Monash Health (AU), Dana-Farber/Harvard Cancer Center (US), University of Pittsburgh Medical Center (US), National Cancer Institute (US), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Melbourne Health (AU), Centre international de recherche sur le cancer (FR), Imperial College London (GB), Monash University (AU), Case Western Reserve University (US), Universitat de Barcelona (ES), Umeå University (SE)
U.S. Department of Health and Human Services, World Health Organization, Fred Hutchinson Cancer Research Center, Ohio State University, Johns Hopkins University, University of Pittsburgh, Deutsches Krebsforschungszentrum, Broad Institute, Centres de Recerca de Catalunya, Pelotonia, Cancer Research UK, National Institute for Health and Care Research, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Cancerfonden, Generalitat de Catalunya, Knut och Alice Wallenbergs Stiftelse, Ligue Contre le Cancer, Vetenskapsrådet, Ministerio de Ciencia e Innovación, Umeå Universitet, Cancer Research Foundation in Northern Sweden, Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, World Cancer Research Fund, Instituto de Salud Carlos III, European Regional Development Fund, NIHR Imperial Biomedical Research Centre, Ontario Ministry of Research and Innovation, National Human Genome Research Institute, National Cancer Institute, Office of Research Infrastructure Programs, National Institutes of Health
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Genetic factors in colorectal cancer
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