Molecular characterization of borderline and malignant Brenner tumors: implications for pathogenesis and therapeutics

Ovarian borderline (BrBT) and malignant (MBT) Brenner tumors are rare neoplasms frequently exhibiting mucinous metaplasia, yet their molecular drivers are poorly defined. To address this, we performed a clinicopathological and molecular study on two cases each BrBT and MBT by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. Recurrent alterations included CDKN2A/CDKN2B deletion with loss of p16 (3/4 cases), MDM2 amplification with positive immunostaining (2/4), and mutations in KRAS, PIK3CA, and FGFR3. A unique MBT with concurrent mucinous adenocarcinoma harboring KRAS/PIK3CA co-mutations followed an aggressive, fatal course. Our analysis and a synthesis of the literature confirm that CDKN2A/CDKN2B deletion and PIK3CA mutation are common in both BrBT and MBT, while MDM2 amplification and KRAS/FGFR3 alterations are enriched in MBT. These findings delineate key molecular drivers, reveal therapeutic vulnerabilities, and underscore the need for molecular-guided strategies in these rare tumors.