title: A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.
abstract: We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: K A W
authors.initials: KA
authors.lastname: Wadt
authors.affiliation: QIMR Berghofer Medical Research Institute, Genetics and Computational Biology, Brisbane, Australia.|University of Queensland, Brisbane, Australia.
authors.forename: L G
authors.initials: LG
authors.lastname: Aoude
authors.affiliation: QIMR Berghofer Medical Research Institute, Genetics and Computational Biology, Brisbane, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Johansson
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Solinas
authors.affiliation: QIMR Berghofer Medical Research Institute, Genetics and Computational Biology, Brisbane, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Pritchard
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: O
authors.initials: O
authors.lastname: Crainic
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: M T
authors.initials: MT
authors.lastname: Andersen
authors.affiliation: Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: J F
authors.initials: JF
authors.lastname: Kiilgaard
authors.affiliation: Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.|Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Heegaard
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Sunde
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Federspiel
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Madore
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.|Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: S W
authors.initials: SW
authors.lastname: McCarthy
authors.affiliation: Department of Cancer Genetics, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Goodwin
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Tsao
authors.affiliation: Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Busam
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: A-M
authors.initials: AM
authors.lastname: Gerdes
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.|Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: QIMR Berghofer Medical Research Institute, Genetics and Computational Biology, Brisbane, Australia.
authors.forename: N K
authors.initials: NK
authors.lastname: Hayward
mesh_terms: D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; 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; D043222:Ubiquitin Thiolesterase
keywords: BAP1; BCC; cancer predisposition syndrome; germline mutation; melanoma; unknown primary tumor