Ovarian sex cord-stromal tumors are part of the BAP1-tumor predisposition syndrome: evidence from human carriers and mouse models

BAP1

Heterozygous germline BAP1 variant with biallelic inactivation in the tumour; reduced Bmpr1b, Erb and Foxl2 expression in mice

The study assesses the association between ovarian cancer and the BAP1-tumor predisposition syndrome (BAP1-TPDS) in two independent cohorts of women carrying a germline pathogenic or likely pathogenic BAP1 variant. Of 176 carriers, 7 (4%) had ovarian cancer, including 3 ovarian sex cord-stromal tumours (OSCST); another OSCST occurred in a patient with a germline variant of conflicting interpretation, whose pathogenicity was supported by functional studies. In mice, OSCSTs occurred in all strains heterozygous for a germline Bap1 mutation, regardless of genetic background (incidence 32-73%). Biallelic BAP1 inactivation was found in 3 of 3 human and 10 of 10 murine OSCSTs. Murine OSCSTs showed marked decreases in Bmpr1b, Erb and Foxl2 expression, suggesting disruption of ovarian differentiation pathways.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

OSCSTs join the BAP1-TPDS spectrum as a rare phenotype, with human-mouse concordance and consistent biallelic inactivation strengthening causality. With 4% ovarian cancer among 176 carriers and only 3 OSCSTs, the data mainly argue for considering BAP1 when facing a sex cord-stromal tumour and taking a family history, rather than immediately instituting dedicated ovarian surveillance.

Analysis by Dr Thibaut Benquey