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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&gt;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).

molecular case studies

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

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