Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease

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INTRODUCTION: Although mesotheliomas are the most common malignancies identified in BAP1 cancer syndrome (BCS), the prevalence and natural history of the neoplasms have not been elucidated. Protocol NCT04431024 was initiated to prospectively evaluate whether high-resolution computed tomography (CT) imaging and minimally invasive surgical evaluation could facilitate detection and surveillance of mesotheliomas in subjects with germline BAP1 mutations. METHODS: Subjects above or equal to 33 years of age with or without prior malignancies underwent CT imaging followed by bilateral thoracoscopies and laparoscopies. CT imaging and intraoperative findings were objectively scored; surgical biopsies were interpreted by two expert pathologists. Skin, peripheral blood mononuclear cells, plasma, serum, and tumor biopsies were collected for correlative research studies. RESULTS: A total of 50 subjects with 32 germline BAP1 mutations were enrolled between March 2021 and July 2024. Median follow-up was 21.8 months (range: 1.7-41.1 mo). Furthermore, 16 sites of prior mesothelioma in 15 patients were excluded from the analysis. Surgical evaluation identified diffuse mesotheliomas in 39 of 45 subjects (87%), affecting 63 of 81 hemi-thoraces (78%) and 27 of 32 peritoneal cavities (84%); these mesotheliomas exhibited unique histologic features and slow clinical progression without therapeutic interventions. CT scans were unreliable for detecting or ruling out these mesotheliomas. Common and mutation specific, cancer-associated epigenomic alterations were identified in dermal fibroblasts and peripheral blood mononuclear cells, which correlated with cancer predilection in subjects with BCS. CONCLUSIONS: Adult subjects with germline BAP1 mutations exhibit a high prevalence of subclinical, multicompartment mesotheliomas, which may be manifestations of systemic epigenetic burdens. These findings establish a paradigm for longitudinal assessment of subjects with BCS and support further efforts to identify and validate epigenetic biomarkers for the detection and surveillance of mesotheliomas and other malignancies arising in these individuals.

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