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

Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2):a003681. doi: 10.1101/mcs.a003681. Print 2019 Apr.


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).

Trial registration: NCT02155621.

Keywords: neoplasm of the breast; neoplasm of the pancreas; pancreatic adenocarcinoma.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Breast Neoplasms / genetics*
  • Carcinoma, Pancreatic Ductal / genetics*
  • DNA Glycosylases / deficiency
  • DNA Glycosylases / genetics*
  • Female
  • Germ-Line Mutation
  • Humans
  • Loss of Heterozygosity
  • Middle Aged
  • Mutation*
  • Pancreatic Neoplasms / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics


  • KRAS protein, human
  • DNA Glycosylases
  • mutY adenine glycosylase
  • Proto-Oncogene Proteins p21(ras)

Associated data


Grant support