title: Germline BAP1 alterations in familial uveal melanoma.
abstract: Uveal melanoma (UM) is the most commonly diagnosed primary intraocular tumor in adults. Familial UM (FUM), defined as two or more family members diagnosed with UM, is rare and estimated at less than 1% of all UM. Currently, BAP1 is the only gene known to contribute significant risk for UM. In this study we aimed to estimate the frequency of BAP1 mutation in FUM and to characterize the family and personal histories of other cancers in these families. We identified 32 families with FUM, including seven families previously reported by our group. BAP1 mutation testing was carried out by direct sequencing of the coding exons and the adjacent untranslated regions of the gene. Germline deletion and duplication analysis of BAP1 was assessed by multiplex ligation-dependent probe amplification (MLPA). Germline BAP1 mutations were found in 6/32 (19%) families. No deletions or duplications were identified in any of the 24 samples tested by MLPA. Combined with published studies, the frequency of BAP1 mutations was 14/64 (22%) in FUM. FUM families without BAP1 mutations have distinct family histories with high rates of prostate cancer in first- and second-degree relatives. It is likely that additional genes conferring risk for FUM exist. It is important to understand key shared features of FUM to focus future research on identifying these additional tumor predisposition syndromes. Though BAP1 should be tested first in these families, FUM families without BAP1 mutation should be explored for additional predisposition genes. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Karan
authors.initials: K
authors.lastname: Rai
authors.affiliation: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Robert
authors.initials: R
authors.lastname: Pilarski
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Getachew
authors.initials: G
authors.lastname: Boru
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Rehman
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Ahmad H
authors.initials: AH
authors.lastname: Saqr
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: James B
authors.initials: JB
authors.lastname: Massengill
authors.affiliation: Cole Eye Institute, Department of Ophthalmic Oncology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Arun
authors.initials: A
authors.lastname: Singh
authors.affiliation: Cole Eye Institute, Department of Ophthalmic Oncology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Marino
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Davidorf
authors.affiliation: Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Cebulla
authors.affiliation: Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Mohamed
authors.identifier: 0000-0002-9493-7894
authors.initials: M
authors.lastname: H Abdel-Rahman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D010375:Pedigree; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase