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Genomic characterization of colorectal tumors: insights into significantly mutated genes, pathways, and survival outcomes.

Authors

Harrison TA, Zaidi SH, Yin H, Steinfelder RS, Qu C, Aglago EK, Berndt SI, Boardman LA, Brenner H, Buchanan DD, Campbell PT, Cao Y, Chan AT, Chanock SJ, Doheny KF, Drew DA, Figueiredo JC, French AJ, Gallinger S, Georgeson P, ...show more Giannakis M, Goode EL, Gruber SB, Gsur A, Gunter MJ, Harlid S, Hoffmeister M, Huang WY, Hullar MA, Huyghe JR, Jenkins MA, Lin Y, Moreno V, Murphy N, Newcomb PA, Newton CC, Nowak JA, Obón-Santacana M, Ogino S, Shelford T, Song M, Thomas CE, Toland AE, Ugai T, Um CY, Van Guelpen B, Trinh QM, Sun W, Hudson TJ, Hsu L, Peters U, Phipps AI

Affiliations

  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. haratabi@uw.edu.
  • Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, USA.
...show more
  • Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Department of Laboratory Medicine and Pathology, Division of Laboratory Genetics, Mayo Clinic, Rochester, MN, USA.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
  • Department of Medical Oncology and Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
  • Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • Department of Diagnostics and Intervention, Oncology Unit, Umeå University, Umeå, Sweden.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Oncology Data Analytics Program (ODAP), Unit of Biomarkers and Suceptibility (UBS), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  • Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. upeters@fredhutch.org.

Abstract

BACKGROUND: Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers.

METHODS: In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons (n = 4,874).

RESULTS: We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P = 2.07 × 10- 10), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P = 1.79 × 10- 12). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P = 7.96 × 10- 4), RTK/RAS (HR 1.33, P = 3.81 × 10- 6), TGF-beta (HR 1.25, P = 1.85 × 10- 3), and WNT (HR 0.81, P = 2.52 × 10- 03).

CONCLUSIONS: We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.

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Publication Details

PubMed ID
41413856

Digital Object Identifier
10.1186/s12885-025-15440-x

Publication
BMC Cancer. 2025 Dec 18; Volume 26 (Issue 1): Pages 109

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