Details

Autor(en) / Beteiligte

• Thibodeau, My Linh
• Zhao, Eric Y
• Reisle, Caralyn
• Ch'ng, Carolyn
• Wong, Hui-Li
• Shen, Yaoqing
• Jones, Martin R
• Lim, Howard J
• Young, Sean
• Cremin, Carol
• Pleasance, Erin
• Zhang, Wei
• Holt, Robert
• Eirew, Peter
• Karasinska, Joanna
• Kalloger, Steve E
• Taylor, Greg
• Majounie, Elisa
• Bonakdar, Melika
• Zong, Zusheng
• Bleile, Dustin
• Chiu, Readman
• Birol, Inanc
• Gelmon, Karen
• Lohrisch, Caroline
• Mungall, Karen L
• Mungall, Andrew J
• Moore, Richard
• Ma, Yussanne P
• Fok, Alexandra
• Yip, Stephen
• Karsan, Aly
• Huntsman, David
• Schaeffer, David F
• Laskin, Janessa
• Marra, Marco A
• Renouf, Daniel J
• Jones, Steven J M
• Schrader, Kasmintan A

Titel

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

Ist Teil von

• Cold Spring Harbor molecular case studies, 2019-04, Vol.5 (2), p.a003681

Ort / Verlag

United States: Cold Spring Harbor Laboratory Press

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic germline mutations, whose tumor featured somatic mutational signatures consistent with defective -mediated base excision repair and the associated driver transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases ( = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline 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 variant with a somatic 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 is not sufficient for C:G>A:T transversion signatures previously linked to deficiency to arise ( = 9), but that biallelic complete loss of function can cause such signatures to arise even in tumors not classically seen in -associated polyposis ( = 3). Although defective is not the only determinant of these signatures, germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36).