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. Using the trio exome sequencing strategy, we identified a germline de novo mutation of the INHBA gene in a patient who developed sporadic bilateral ovarian epithelial adenocarcinomas at 21 years of age and showed that this mutation affects the inhibin/activin ratio. Identification in patients with early‐onset ovarian tumors of other variations affecting this gene or its partner INHA, functional assays and statistical tests indicate that germline alterations of the inhibin/activin pathway may contribute to the genetic determinism of early‐onset epithelial ovarian tumors.