Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis
Autor: | Elisa Majounie, Dustin Bleile, Zusheng Zong, Wei Zhang, Eric Y. Zhao, Karen A. Gelmon, Martin R. Jones, Marco A. Marra, Peter Eirew, Sean D. Young, Yaoqing Shen, David G. Huntsman, Steven J.M. Jones, Steve E. Kalloger, Robert A. Holt, Stephen Yip, Janessa Laskin, My Linh Thibodeau, Daniel J. Renouf, Readman Chiu, Aly Karsan, Karen Mungall, Inanc Birol, Caralyn Reisle, Carol Cremin, Greg Taylor, Yussanne Ma, Kasmintan A. Schrader, Carolyn Ch'ng, Joanna M. Karasinska, Howard John Lim, Alexandra Fok, Andrew J. Mungall, David F. Schaeffer, Erin Pleasance, Melika Bonakdar, Hui-Li Wong, Caroline Lohrisch, Richard D. Moore |
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Rok vydání: | 2019 |
Předmět: |
0303 health sciences
Somatic cell Heterozygote advantage General Medicine Biology medicine.disease_cause Germline 03 medical and health sciences 0302 clinical medicine Germline mutation MUTYH 030220 oncology & carcinogenesis medicine Cancer research KRAS Carcinogenesis Transversion 030304 developmental biology |
Zdroj: | Molecular Case Studies. 5:a003681 |
ISSN: | 2373-2873 2373-2865 |
Popis: | We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic MUTYH germline mutations, whose tumor featured somatic mutational signatures consistent with defective MUTYH-mediated base excision repair and the associated driver KRAS transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases (N = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline MUTYH heterozygote carriers or if instead the signatures were only seen in those with biallelic loss of function. We identified two patients with breast cancer each carrying a pathogenic germline MUTYH variant with a somatic MUTYH copy loss leading to the germline variant being homozygous in the tumor and demonstrating the same somatic signatures. Our results suggest that monoallelic inactivation of MUTYH is not sufficient for C:G>A:T transversion signatures previously linked to MUTYH deficiency to arise (N = 9), but that biallelic complete loss of MUTYH function can cause such signatures to arise even in tumors not classically seen in MUTYH-associated polyposis (N = 3). Although defective MUTYH is not the only determinant of these signatures, MUTYH germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of MUTYH deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36). |
Databáze: | OpenAIRE |
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