title: Inference on germline BAP1 mutations and asbestos exposure from the analysis of familial and sporadic mesothelioma in a high-risk area.
abstract: Inherited loss-of-function mutations in the BAP1 oncosuppressor gene are responsible for an inherited syndrome with predisposition to malignant mesothelioma (MM), uveal and keratinocytic melanoma, and other malignancies. Germline mutations that were inherited in an autosomal dominant fashion were identified in nine families with multiplex MM cases and 25 families with multiple melanoma, renal cell carcinoma, and other tumors. Germline mutations were also identified in sporadic MM cases, suggesting that germline mutations in BAP1 occur frequently. In this article, we report the analysis of BAP1 in five multiplex MM families and in 103 sporadic cases of MM. One family carried a new truncating germline mutation. Using immunohistochemistry, we show that BAP1 is not expressed in tumor tissue, which is in accordance with Knudson's two hits hypothesis. Interestingly, whereas the three individuals who were possibly exposed to asbestos developed MM, the individual who was not exposed developed a different tumor type, that is, mucoepidermoid carcinoma. This finding suggests that the type of carcinogen exposure may be important for the cancer type that is developed by mutation carriers. On the contrary, the other families or the 103 sporadic patients did not show germline mutations in BAP1. Our data show that BAP1 mutations are very rare in patients with sporadic MM, and we report a new BAP1 mutation, extend the cancer types associated with these mutations, and suggest the existence of other yet unknown genes in the pathogenesis of familial MM.
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Betti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Casalone
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferrante
authors.forename: Antonio
authors.initials: A
authors.lastname: Romanelli
authors.forename: Federica
authors.initials: F
authors.lastname: Grosso
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
authors.forename: Simona
authors.initials: S
authors.lastname: Vatrano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Roberta
authors.initials: R
authors.lastname: Libener
authors.forename: Dario
authors.initials: D
authors.lastname: Mirabelli
authors.forename: Renzo
authors.initials: R
authors.lastname: Boldorini
authors.forename: Caterina
authors.initials: C
authors.lastname: Casadio
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Corrado
authors.initials: C
authors.lastname: Magnani
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
mesh_terms: D000328:Adult; D000368:Aged; D001194:Asbestos / Q000633:toxicity*; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D004785:Environmental Pollutants; D025521:Tumor Suppressor Proteins; D001194:Asbestos; D043222:Ubiquitin Thiolesterase