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Title: Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas: Mutational signature associated with MUTYH deficiency in cancers

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Altogether, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types.
ORCiD logo [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [6] ;  [1] ;  [2] ;  [6] ;  [4] ;  [2] ;  [1]
  1. INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris France
  2. INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer Paris France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité Paris France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH) Bobigny France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris France
  3. Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos NM USA; Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos NM USA
  4. INSERM U1016, CNRS UMR 8104, Paris Descartes University, Institut Cochin, Paris France; Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris France
  5. Department of Medical Oncology AP-HP, Hospital Saint-Antoine, Paris France; Université Pierre et Marie Curie (UMPC) Paris VI, Paris France
  6. Department of Pathology AP-HP, Hôpital Ambroise Paré, Paris France; EA 4340, Université de Versailles, Versailles France
Publication Date:
Report Number(s):
Journal ID: ISSN 0022-3417
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Journal of Pathology
Additional Journal Information:
Journal Volume: 242; Journal Issue: 1; Journal ID: ISSN 0022-3417
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1401046