title: CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.
abstract: BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Betti
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Aspesi
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biasi
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, HuGeF, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Casalone
authors.affiliation: CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ferrante
authors.affiliation: Medical Genetics Unit, AOU Città della Salute e della Scienza, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ogliara
authors.affiliation: Dermatology Clinic, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: L C
authors.initials: LC
authors.lastname: Gironi
authors.affiliation: Dermatology Clinic, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Giorgione
authors.affiliation: Dermatology Clinic, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Farinelli
authors.affiliation: Division of Medical Oncology, SS.Antonio e Biagio General Hospital, Alessandria, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grosso
authors.affiliation: Pathology Unit, SS.Antonio e Biagio General Hospital, Alessandria, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Libener
authors.affiliation: Department of Obstetric, Gynecologic and Pediatric, Section of Clinical Genetics, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rosato
authors.affiliation: Medical Genetics, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Turchetti
authors.affiliation: Molecular Genetics and Biology Unit, Santa Croce e Carle Hospital, Cuneo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Maffè
authors.affiliation: Thoracic Surgery Unit, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Casadio
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Ascoli
authors.affiliation: Department of Dermatology, Campus Biomedico, University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Dermatology Clinic, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Colombo
authors.affiliation: Pneumology Unit, Santo Spirito Hospital, Casale Monferrato, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Piccolini
authors.affiliation: Pathological Anatomy Unit, Santo Spirito Hospital, Casale Monferrato, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pavesi
authors.affiliation: Medical Genetics, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Miccoli
authors.affiliation: Unit of Cancer Epidemiology, CPO-Piemonte and University of Turin, Turin, Italy; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Mirabelli
authors.affiliation: Medical Genetics Unit, AOU Città della Salute e della Scienza, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bracco
authors.affiliation: Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Righi
authors.affiliation: Department of Health Sciences, Section of Pathological Anatomy, University of Piemonte Orientale, Novara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Boldorini
authors.affiliation: Department of Oncology, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, HuGeF, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Matullo
authors.affiliation: CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Magnani
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy; Medical Genetics Unit, AOU Città della Salute e della Scienza, Turin, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pasini
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale, Novara, Italy; Interdepartmental Center for Studies on Asbestos and other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy. Electronic address: irma.dianzani@med.uniupo.it.
authors.forename: I
authors.initials: I
authors.lastname: Dianzani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D018389:Codon, Nonsense; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D016208:Databases, Factual; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008297:Male; D008545:Melanoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D012878:Skin Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics*; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D018389:Codon, Nonsense; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: Asbestos exposure; Cancer predisposition syndrome; Carcinogenesis