title: Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer.
abstract: Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.
authors.affiliation: Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, North Caroline. joseph.testa@fccc.edu johar@wfubmc.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Ohar
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Talarchek
authors.affiliation: Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, North Caroline.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Howard
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Caroline.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Howard
authors.affiliation: Mesothelioma Applied Research Foundation, Alexandria, Virginia.
authors.forename: Mary
authors.initials: M
authors.lastname: Hesdorffer
authors.affiliation: Gene Expression and Regulation Program, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.affiliation: Gene Expression and Regulation Program, Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. joseph.testa@fccc.edu johar@wfubmc.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D001194:Asbestos / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008654:Mesothelioma / Q000209:etiology / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D020125:Mutation, Missense; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D001194:Asbestos; D043222:Ubiquitin Thiolesterase