2026-04-13T07:00:26Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1870552025-12-05T12:17:53Zcom_2072_1057col_2072_478916col_2072_478917

urn:hdl:2445/187055 Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures Georgeson, Peter Harrison, Tabitha A. Pope, Bernard J. Zaidi, Syed H. Qu, Conghui Steinfelder, Robert S. Lin, Yi Joo, Jihoon E. Mahmood, Khalid Clendenning, Mark Walker, Romy Amitay, Efrat L. Berndt, Sonja I. Brenner, Hermann Campbell, Peter T. Cao, Yin Chan, Andrew T. Chang-Claude, Jenny Doheny, Kimberly F. Drew, David A. Figueiredo, Jane C. French, Amy J. Gallinger, Steven Giannakis, Marios Giles, Graham G. Gsur, Andrea Gunter, Marc J. Hoffmeister, Michael Hsu, Li Huang, Wen-Yi Limburg, Paul Manson, Joann E. Moreno Aguado, Víctor Nassir, Rami Nowak, Jonathan A. Obón Santacana, Mireia Ogino, Shuji Phipps, Amanda I. Potter, John D. Schoen, Robert E. Sun, Wei Toland, Amanda E. Trinh, Quang M. Ugai, Tomotaka Macrae, Finlay Rosty, Christophe Hudson, Thomas J. Jenkins, Mark A. Thibodeau, Stephen N. Winship, Ingrid M. Peters, Ulrike Buchanan, Daniel D. Càncer colorectal Genètica Colorectal cancer Genetics 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 x 10(-23) and p = 6 x 10(-11), respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers. Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations. 2022-06-27T10:24:30Z 2022-06-27T10:24:30Z 2022-06-06 2022-06-27T07:57:53Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-30916-1 Nature Communications, 2022, vol. 13, num. 1 https://doi.org/10.1038/s41467-022-30916-1 cc by (c) Georgeson, Peter et al, 2022 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Springer Science Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))