title: Germline mutations of inhibins in early-onset ovarian epithelial tumors.
abstract: To identify novel genetic bases of early-onset epithelial ovarian tumors, we used the trio exome sequencing strategy in a patient without familial history of cancer who presented metastatic serous ovarian adenocarcinomas at 21 years of age. We identified a single de novo mutation (c.1157A>G/p.Asn386Ser) within the INHBA gene encoding the βA-subunit of inhibins/activins, which play a key role in ovarian development. In vitro, this mutation alters the ratio of secreted activins and inhibins. In a second patient with early-onset serous borderline papillary cystadenoma, we identified an unreported germline mutation (c.179G>T/p.Arg60Leu) of the INHA gene encoding the α-subunit, the partner of the βA-subunit. This mutation also alters the secreted activin/inhibin ratio, by disrupting both inhibin A and inhibin B biosynthesis. In a cohort of 62 cases, we detected an additional unreported germline mutation of the INHBA gene (c.839G>A/p.Gly280Glu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, Cancéropôle Nord-Ouest, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tournier
authors.forename: Régine
authors.initials: R
authors.lastname: Marlin
authors.forename: Kelly
authors.initials: K
authors.lastname: Walton
authors.forename: Françoise
authors.initials: F
authors.lastname: Charbonnier
authors.forename: Sophie
authors.initials: S
authors.lastname: Coutant
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Théry
authors.forename: Camille
authors.initials: C
authors.lastname: Charbonnier
authors.forename: Cailyn
authors.initials: C
authors.lastname: Spurrell
authors.forename: Myriam
authors.initials: M
authors.lastname: Vezain
authors.forename: Lorena
authors.initials: L
authors.lastname: Ippolito
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bougeard
authors.forename: Horace
authors.initials: H
authors.lastname: Roman
authors.forename: Julie
authors.initials: J
authors.lastname: Tinat
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Dominique
authors.initials: D
authors.lastname: Vaur
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Craig
authors.initials: C
authors.lastname: Harrison
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
mesh_terms: D028341:Activins / Q000096:biosynthesis; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation; D015331:Cohort Studies; D004847:Epithelial Cells / Q000378:metabolism; D059472:Exome; D005260:Female; D018095:Germ-Line Mutation; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics*; D007265:Inhibins / Q000096:biosynthesis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C422362:inhibin A; C422364:inhibin B; C103008:inhibin beta A subunit; D028341:Activins; D007265:Inhibins; D028322:Inhibin-beta Subunits
keywords: INHA; INHBA; activin; cancer; exome; inhibin; ovary