Broadening Our Knowledge of the BAP1 Tumor Predisposition Syndrome

Alexandra Lebensohn, Grace Fasaye, Maria Gracia Agra, Yvonne Mallory, Cathy Wagner, Rosemary Bekker, Azam Ghafoor, Kathleen Calzone, Raffit Hassan

There is still much to learn about hereditary malignant mesothelioma, historically attributed primarily to asbestos exposure. Hassan et al. demonstrated that germline DNA repair pathogenic variants are present in approximately 12% of malignant mesothelioma cases in a cohort of 385 patients. By far, the largest contributor to this hereditary risk is the BAP1 (BRCA1-associated Protein 1) gene. BAP1 is a tumor suppressor gene on chromosome 3p21.31-p21.2 involved in DNA repair, cell growth and cell cycle regulation. Pleural mesothelioma patients with BAP1 pathogenic variants have a significantly increased median overall survival compared to wildtype mesothelioma patients (7.9 years vs 2.4 years, p=0.001), making genetic testing a valuable prognostic tool. Individuals with germline BAP1 pathogenic variants have BAP1 Tumor Predisposition Syndrome (BTPDS) associated with a significantly increased risk for mesothelioma, as well as other cancers including uveal melanoma, cutaneous melanoma, renal cell carcinomas, basal cell carcinomas, breast cancer, cholangiocarcinoma and meningioma. Our NIH team has initiated a unique opportunity for individuals with BAP1 pathogenic variants to centralize surveillance for these high-risk cancers and be followed longitudinally using a robust screening protocol (19-C0049). Participants receive expert care and consultation every year by a team of providers who are knowledgeable about their genetic condition, allowing for comprehensive discussion of any updates and breakthroughs regarding BTPDS. Through genetic counseling, personal and family history is extensively documented to understand clinical manifestations and penetrance of the syndrome. Cascade genetic testing is offered to 1st and 2nd degree family members to further identify at-risk relatives and personalize management recommendations within families. Psychosocial issues such as survivor’s guilt, concern for children and fear of environmental triggers are addressed. BAP1 carriers are physically screened yearly at the NIH by comprehensive dermatological and ophthalmological exams, as well as bloodwork and urine cytology. Every 2 years, participants receive brain, chest, abdominal, pelvic and breast MRI. As a team, we are working to develop a comprehensive database of screening results to efficiently track possible precursors to cancers. Patients receive a coordinated management plan which optimizes early detection strategies. This consolidated approach enables the team to characterize the natural and clinical history of malignant mesothelioma patients and family members with germline pathogenic variants in BAP1 and other DNA repair genes.

PI: Kathy Calzone