title: A population-based analysis of germline BAP1 mutations in melanoma.
abstract: Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: O'Shea
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.|Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Juriquilla 76230, Santiago de Querétaro, Qro, Mexico.
authors.forename: Carla Daniela
authors.initials: CD
authors.lastname: Robles-Espinoza
authors.affiliation: MISSION Therapeutics, Babraham Research Campus. Moneta (Building 280). Cambridge, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: McLellan
authors.affiliation: MISSION Therapeutics, Babraham Research Campus. Moneta (Building 280). Cambridge, UK.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Harrigan
authors.affiliation: MISSION Therapeutics, Babraham Research Campus. Moneta (Building 280). Cambridge, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jacq
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
authors.forename: James
authors.initials: J
authors.lastname: Hewinson
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Histopathology Department, Bexley Wing, St. James's University Hospital, Leeds, UK.
authors.forename: Will
authors.initials: W
authors.lastname: Merchant
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Faye
authors.initials: F
authors.lastname: Elliott
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Newton-Bishop
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D018095:Germ-Line Mutation / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase