Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members

Abstract

Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma and other cancers. We describe a patient with a family history of peritoneal mesothelioma, who developed malignant peritoneal mesothelioma at age 45 in the absence of known asbestos exposure. These findings lead us to hypothesize that the mesothelioma occurred in the setting of germline a BAP1 mutation. This was confirmed by genetic testing. The subsequent therapeutic choices for the patient and testing of at-risk family members highlight the importance of recognizing this genetic syndrome and screening for individuals at high risk.

Malignant Peritoneal Mesothelioma as a Rare Cause of Dyspeptic Complaints and Ascites: A Diagnostic Challenge

“…The most common are pleural and peritoneal mesotheliomas, uveal and cutaneous melanomas, and renal cell carcinomas. Testing for BAP1 mutations should be made in patients with mesothelioma occurring at a young age (< 50 years old) and in patients with multiple family members affected by mesothelioma or other cancers associated with germline BAP1 mutations [10]. In our patient, the search for germline BAP1 mutation was not done because he had only one family member (his brother) with the diagnosis of MPM and also because his brother had a heavier expo- sure history to asbestos (> 10 years).…”

Biomarkers Progress and Therapeutic Implications in Malignant Mesothelioma

“…BAP1 has been shown to have different tumor-suppressing functions when localized to the nucleus vs. cytoplasm. In the nucleus, it is promoted to double-stranded DNA break sites to aid in repair via homologous recombination, therefore inhibiting the growth of the damaged, mutated DNA [31,32]. In the cytoplasm, BAP1 deubiquitylates type-3 inositol-1,4,5-trisphosphate-receptor (IP3R3) on the endoplasmic reticulum (ER).…”

“…Once stabilized, IP3R3 allows the efflux of calcium (Ca 2+ ) from the ER into the cytoplasm. This increase in Ca 2+ promotes cytochrome c activation and induces cell apoptosis [32,33]. More recently, it has been proposed that BAP1 also regulates ferroptosis, an iron-dependent programmed cell death via the repression of cystine transporter SLC7A11 [34].…”

“…Germline mutations in BAP1 are associated with a novel cancer syndrome named "BAP1 Cancer Syndrome." This syndrome infers increased susceptibility to a variety of malignancies including mesothelioma, uveal and skin melanoma, cholangiocarcinoma, renal cell, basal cell, and squamous cell carcinomas, among others [32]. Malignant mesotheliomas that develop in BAP1 germline mutation carriers tend to be less aggressive with better prognosis and improved survival compared to sporadic mesothelioma [46].…”

Genetic predisposition for malignant mesothelioma: A concise review

“…Patients with uveal melanoma and germline variants in BAP1 have a bad prognosis [29,32], whereas patients with mesothelioma and germline variants in BAP1 seem to have a longer survival than those without these variants [33][34][35]. So far, only 182 families with BAP1-TPDS have been identified, but the penetrance of the defect has not yet been calculated [30][31][32][33][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. On the other hand, it is well known that these patients may develop more than one tumor.…”