Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Peter Georgeson, Tabitha A. Harrison, Bernard J. Pope, Syed H. Zaidi, Conghui Qu, Robert S. Steinfelder, Yi Lin, Jihoon E. Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Efrat L. Amitay, Sonja I. Berndt, Hermann Brenner, Peter T. Campbell, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Kimberly F. Doheny, David A. Drew, Jane C. Figueiredo, Amy J. French, Steven Gallinger, Marios Giannakis, Graham G. Giles, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Paul Limburg, JoAnn E. Manson, Victor Moreno, Rami Nassir, Jonathan A. Nowak, Mireia Obón-Santacana, Shuji Ogino, Amanda I. Phipps, John D. Potter, Robert E. Schoen, Wei Sun, Amanda E. Toland, Quang M. Trinh, Tomotaka Ugai, Finlay A. Macrae, Christophe Rosty, Thomas J. Hudson, Mark A. Jenkins, Stephen N. Thibodeau, Ingrid M. Winship, Ulrike Peters and Daniel D. Buchanan ()
Additional contact information
Peter Georgeson: The University of Melbourne
Tabitha A. Harrison: Fred Hutchinson Cancer Research Center
Bernard J. Pope: The University of Melbourne
Syed H. Zaidi: Ontario Institute for Cancer Research
Conghui Qu: Fred Hutchinson Cancer Research Center
Robert S. Steinfelder: Fred Hutchinson Cancer Research Center
Yi Lin: Fred Hutchinson Cancer Research Center
Jihoon E. Joo: The University of Melbourne
Khalid Mahmood: The University of Melbourne
Mark Clendenning: The University of Melbourne
Romy Walker: The University of Melbourne
Efrat L. Amitay: German Cancer Research Center (DKFZ)
Sonja I. Berndt: National Cancer Institute, National Institutes of Health
Hermann Brenner: German Cancer Research Center (DKFZ)
Peter T. Campbell: Albert Einstein College of Medicine
Yin Cao: Washington University School of Medicine
Andrew T. Chan: Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Kimberly F. Doheny: Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine
David A. Drew: Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School
Jane C. Figueiredo: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Amy J. French: Mayo Clinic
Steven Gallinger: Ontario Institute for Cancer Research
Marios Giannakis: Broad Institute of MIT and Harvard
Graham G. Giles: Cancer Epidemiology Division, Cancer Council Victoria
Andrea Gsur: Institute of Cancer Research, Department of Medicine I, Medical University Vienna
Marc J. Gunter: Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization
Michael Hoffmeister: German Cancer Research Center (DKFZ)
Li Hsu: Fred Hutchinson Cancer Research Center
Wen-Yi Huang: National Cancer Institute, National Institutes of Health
Paul Limburg: Mayo Clinic
JoAnn E. Manson: Harvard T.H. Chan School of Public Health
Victor Moreno: Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat
Rami Nassir: Umm Al-Qura University
Jonathan A. Nowak: Brigham and Women’s Hospital, Harvard Medical School
Mireia Obón-Santacana: Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat
Shuji Ogino: Broad Institute of MIT and Harvard
Amanda I. Phipps: Fred Hutchinson Cancer Research Center
John D. Potter: Fred Hutchinson Cancer Research Center
Robert E. Schoen: University of Pittsburgh Medical Center
Wei Sun: Fred Hutchinson Cancer Research Center
Amanda E. Toland: Comprehensive Cancer Center, The Ohio State University
Quang M. Trinh: Ontario Institute for Cancer Research
Tomotaka Ugai: Harvard T.H. Chan School of Public Health
Finlay A. Macrae: Parkville Familial Cancer Centre, Royal Melbourne Hospital
Christophe Rosty: The University of Melbourne
Thomas J. Hudson: Ontario Institute for Cancer Research
Mark A. Jenkins: University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre
Stephen N. Thibodeau: Mayo Clinic
Ingrid M. Winship: Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital
Ulrike Peters: Fred Hutchinson Cancer Research Center
Daniel D. Buchanan: The University of Melbourne

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30916-1

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