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Germline Mutations of Inhibins in Early‐Onset Ovarian Epithelial Tumors
Author(s) -
Tournier Isabelle,
Marlin Régine,
Walton Kelly,
Charbonnier Françoise,
Coutant Sophie,
Théry JeanChristophe,
Charbonnier Camille,
Spurrell Cailyn,
Vezain Myriam,
Ippolito Lorena,
Bougeard Gaëlle,
Roman Horace,
Tinat Julie,
Sabourin JeanChristophe,
StoppaLyonnet Dominique,
Caron Olivier,
Bressacde Paillerets Brigitte,
Vaur Dominique,
King MaryClaire,
Harrison Craig,
Frebourg Thierry
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22489
Subject(s) - biology , germline , mutation , ovary , inha , germline mutation , serous fluid , medicine , endocrinology , gene , cancer research , genetics , pathology , tuberculosis , biochemistry , isoniazid
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.1157 A > G /p. A sn386 S er) within the INHBA gene encoding the β A ‐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.179 G > T /p. A rg60 L eu) of the INHA gene encoding the α‐subunit, the partner of the β A ‐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.839 G > A /p. G ly280 G lu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors.