title: Germline BAP1 mutations predispose to malignant mesothelioma.
abstract: Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. joseph.testa@fccc.edu
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: Mitchell
authors.initials: M
authors.lastname: Cheung
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: Yinfei
authors.initials: Y
authors.lastname: Tan
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sementino
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: A Umran
authors.initials: AU
authors.lastname: Dogan
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Sandra
authors.initials: S
authors.lastname: Trusa
authors.forename: Mary
authors.initials: M
authors.lastname: Hesdorffer
authors.forename: Masaki
authors.initials: M
authors.lastname: Nasu
authors.forename: Amy
authors.initials: A
authors.lastname: Powers
authors.forename: Zeyana
authors.initials: Z
authors.lastname: Rivera
authors.forename: Sabahattin
authors.initials: S
authors.lastname: Comertpay
authors.forename: Mika
authors.initials: M
authors.lastname: Tanji
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
mesh_terms: D001194:Asbestos / Q000633:toxicity; D004781:Environmental Exposure; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D001194:Asbestos; D043222:Ubiquitin Thiolesterase