title: Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas.
abstract: 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. Taken together, 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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.
authors.forename: Camilla
authors.identifier: 0000-0002-1781-5180
authors.initials: C
authors.lastname: Pilati
authors.affiliation: 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.
authors.forename: Jayendra
authors.initials: J
authors.lastname: Shinde
authors.affiliation: 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.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: 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.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.affiliation: Department of Medical Oncology AP-HP, Hospital Saint-Antoine, Paris, France.|Université Pierre et Marie Curie (UMPC) Paris VI, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: André
authors.affiliation: Department of Pathology AP-HP, Hôpital Ambroise Paré, Paris, France.|EA 4340, Université de Versailles, Versailles, France.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Hélias-Rodzewicz
authors.affiliation: Department of Pathology AP-HP, Hôpital Ambroise Paré, Paris, France.|EA 4340, Université de Versailles, Versailles, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Ducoudray
authors.affiliation: INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Corre
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: Department of Pathology AP-HP, Hôpital Ambroise Paré, Paris, France.|EA 4340, Université de Versailles, Versailles, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D018345:Mice, Knockout; D009154:Mutation; D059467:Transcriptome / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase
keywords: MUTYH; adrenocortical carcinomas; colorectal cancer; mutational signatures