malignant mesothelioma and overall survival following platinum chemotherapy

Malignant mesothelioma is an aggressive tumor arising from the mesothelial cells lining the pleura, peritoneum, pericardium, or tunica vaginalis, with ∼3,000 cases diagnosed each year in the United States (1). Asbestos is the principal carcinogen associated with mesothelioma development, with exposure to other minerals such as erionite also causally implicated (1, 2). Mesothelioma can also develop in patients who have received radiation therapy for another cancer (3). Inherited loss-of-function mutations in BAP1 (BRCA1-associated protein) predispose to mesothelioma (4–7), as well as to other conditions (8) including uveal melanoma (9), cutaneous melanoma (10), meningioma (11), basal cell carcinoma (12), and renal cell carcinoma (13). BAP1 encodes a deubiquitinase that binds to BRCA1 and BARD1 and enhances their tumor suppressor function (14). It has been suggested that BAP1 is involved in homologous recombination DNA repair by cleaving ubiquitin from histone 2A at a critical step in the process (15). Inherited loss-of-function mutations in other genes may also predispose to mesothelioma (16–18) with lifetime risks expected to be much lower than risks to carriers of mutations in BAP1. Median overall survival of patients with pleural mesothelioma is especially poor: ∼12–16 mo following treatment with cisplatin plus pemetrexed (19, 20), the first-line standard of care chemotherapy for this disease. Of potential importance to mesothelioma, ovarian and breast cancers that develop in patients with inherited mutations in BRCA1 and BRCA2 are particularly sensitive to cisplatin chemotherapy and, for ovarian cancer, these patients have better overall survival (21–24). BRCA1 and BRCA2 are integral to DNA repair by homologous recombination. Breast, ovarian, and prostate cancers in patients with mutations in BRCA1 or BRCA2 are also more sensitive to poly-ADP ribose polymerase (PARP) inhibitors, which cause cell death by inducing Significance Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with some cancers, overall survival following platinum chemotherapy is better for patients with germline mutations in DNA repair and related genes than for patients without such mutations. We evaluated this relationship for patients with malignant mesothelioma. Following platinum chemotherapy, overall survival was significantly longer for patients with loss-of-function mutations in BAP1 and DNA repair genes compared with patients with no such mutations. The effect of genotype was highly significant for patients with pleural mesothelioma, but not for patients with peritoneal mesothelioma, and remained significant after adjusting for gender and age at diagnosis. These patients may benefit from DNA repair targeted therapies such as poly-ADP ribose polymerase inhibitors. Author contributions: R.H., M.-C.K., and J.E.C. d