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. DrewJane 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, Jo Ann 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, Daniel D. Buchanan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Article number3254
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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