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

Abstract

Germline heterozygous BAP1 pathogenic/likely pathogenic (P/LP) variants are associated with the BAP1-tumor predisposition syndrome (BAP1-TPDS). This study evaluated evidence for an association between ovarian cancers and BAP1-TPDS. We evaluated ovarian cancer incidence in two independent cohorts of female subjects with germline BAP1 P/LP variants. Additionally, we investigated whether the high incidence of spontaneous ovarian sex cord-stromal tumors (OSCSTs) in heterozygous Bap1-mutant FVB/N mice was strain-specific by examining their occurrence in several other Bap1-mutant mouse models with different genetic backgrounds. In the combined human cohort of 176 females with BAP1 P/LP variants, 7 (4%) had ovarian cancer, including 3 with OSCST. Another OSCST occurred in a patient with a germline BAP1 variant with conflicting pathogenesis, for which functional studies supported pathogenicity. OSCSTs were observed in all mouse strains with germline heterozygous Bap1 mutations (incidence: 32%-73%). Biallelic inactivation of BAP1 was observed in 3/3 human and 10/10 murine OSCSTs. OSCSTs from Bap1-mutant mice showed marked decreases in Bmpr1b, Erb, and Foxl2 expression, suggesting disruption of pathways involved in ovarian differentiation and homeostasis. In conclusion, ovarian cancers, particularly OSCSTs, represent a rarer phenotype of the BAP1-TPDS. Downregulation of Bmpr1b, Erb, and Foxl2 may reflect alterations in pathways amenable to therapeutic targeting in OSCSTs.