title: Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
abstract: Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
authors.affiliation: 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA. [2].
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
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authors.affiliation: Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
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authors.affiliation: Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Maria Concetta
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authors.affiliation: 1] Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. [2] Genetics of Rare Hereditary Cancers, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
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authors.affiliation: Service de Génétique, Gustave Roussy, Villejuif, France.
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authors.forename: Eduardo
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authors.affiliation: Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
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authors.forename: Zhaoming
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authors.forename: Xijun
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authors.forename: William
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authors.forename: Lorenza
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authors.forename: Zaida
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authors.affiliation: 1] INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France. [2] Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Amaury
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authors.forename: Mark
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authors.affiliation: Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
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authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
authors.forename: Giovanna Bianchi
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authors.affiliation: Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
authors.forename: Giorgio
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authors.forename: Florence
authors.identifier: 0000000183610936
authors.initials: F
authors.lastname: Demenais
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
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authors.forename: Alisa M
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mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019295:Computational Biology; D059472:Exome / Q000235:genetics; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007558:Italy; D008545:Melanoma / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009372:Neoplasms, Connective Tissue / Q000235:genetics*; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D000089804:Shelterin Complex; D012878:Skin Neoplasms; D059505:Telomere Homeostasis / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D014481:United States; D000096142:Cutaneous Malignant Melanoma
chemical_list: C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins