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Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis.


ABSTRACT: 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).

SUBMITTER: Thibodeau ML 

PROVIDER: S-EPMC6549570 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Base excision repair deficiency signatures implicate germline and somatic <i>MUTYH</i> aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis.

Thibodeau My Linh ML   Zhao Eric Y EY   Reisle Caralyn C   Ch'ng Carolyn C   Wong Hui-Li HL   Shen Yaoqing Y   Jones Martin R MR   Lim Howard J HJ   Young Sean S   Cremin Carol C   Pleasance Erin E   Zhang Wei W   Holt Robert R   Eirew Peter P   Karasinska Joanna J   Kalloger Steve E SE   Taylor Greg G   Majounie Elisa E   Bonakdar Melika M   Zong Zusheng Z   Bleile Dustin D   Chiu Readman R   Birol Inanc I   Gelmon Karen K   Lohrisch Caroline C   Mungall Karen L KL   Mungall Andrew J AJ   Moore Richard R   Ma Yussanne P YP   Fok Alexandra A   Yip Stephen S   Karsan Aly A   Huntsman David D   Schaeffer David F DF   Laskin Janessa J   Marra Marco A MA   Renouf Daniel J DJ   Jones Steven J M SJM   Schrader Kasmintan A KA  

Cold Spring Harbor molecular case studies 20190401 2


We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic <i>MUTYH</i> germline mutations, whose tumor featured somatic mutational signatures consistent with defective <i>MUTYH</i>-mediated base excision repair and the associated driver <i>KRAS</i> transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases (<i>N</i> = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline <i>M  ...[more]

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