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Title: Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures
Author: 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 A.
Rosty, Christophe
Hudson, Thomas J.
Jenkins, Mark A.
Thibodeau, Stephen N.
Winship, Ingrid M.
Peters, Ulrike
Buchanan, Daniel D.
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 6-Jun-2022
Publisher: Springer Science
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 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.
Note: Reproducció del document publicat a:
It is part of: Nature Communications, 2022, vol. 13, num. 1
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ISSN: 2041-1723
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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