Skip to Main Content

An official website of the United States government

About this Publication
Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.
Pubmed ID
35668106 (View this publication on the PubMed website)
Digital Object Identifier
Nat Commun. 2022 Jun 6; Volume 13 (Issue 1): Pages 3254
Georgeson P, Harrison TA, Pope BJ, Zaidi SH, Qu C, Steinfelder RS, Lin Y, Joo JE, Mahmood K, Clendenning M, Walker R, Amitay EL, Berndt SI, Brenner H, Campbell PT, Cao Y, Chan AT, Chang-Claude J, Doheny KF, Drew DA, more Figueiredo JC, French AJ, Gallinger S, Giannakis M, Giles GG, Gsur A, Gunter MJ, Hoffmeister M, Hsu L, Huang WY, Limburg P, Manson JE, Moreno V, Nassir R, Nowak JA, Obón-Santacana M, Ogino S, Phipps AI, Potter JD, Schoen RE, Sun W, Toland AE, Trinh QM, Ugai T, Macrae FA, Rosty C, Hudson TJ, Jenkins MA, Thibodeau SN, Winship IM, Peters U, Buchanan DD
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. more
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Department of Pathology, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
  • Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • Parkville Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, Australia.
  • University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
  • Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

Related CDAS Studies
Related CDAS Projects