Identification of BAP1 as a predisposing gene for malignant mesothelioma

Abstract

Malignant mesothelioma (MM) is a very aggressive tumor which arises from mesothelial cells found in the lining of the pleural, pericardial and peritoneal cavities. An estimated 3,000 people are diagnosed with MM each year in the United States and the prognosis is very poor with a median survival of about 12 to 18 months from diagnosis. The relationship between asbestos exposure and mesothelioma is now widely accepted and approximately 80% of patients with MM in the United States have been exposed to asbestos. However, because only a small fraction of asbestos-exposed individuals develop MM (about 5%) and clustering of this disease was observed in some families, we hypothesized the existence of a genetic predisposing factor. We have been searched for mutated genes in germline cells of individuals from "mesothelioma village" in Cappadocia, Turkey, and in two American families, which have history of mesothelioma. We discovered mutations in the gene encoding BRCA1 associated protein-1 (BAP1) from the two American families with a high incidence of MM. We also found germline BAP1 mutations in 2 of 26 sporadic MM; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma, too. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic MM with no germline mutations. This is the first project which proved that BAP1 as a predisposing gene for malignant mesothelioma.