Accepted manuscript
Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma
Nature genetics, Vol.46(5), pp.482-486
05/2014
Handle:
https://hdl.handle.net/2376/106865
PMCID: PMC4056593
PMID: 24686846
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.
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- Title
- Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma
- Creators
- Jianxin Shi - 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.Xiaohong R Yang - 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.Bari Ballew - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAMelissa Rotunno - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USADonato Calista - Department of Dermatology, Maurizio Bufalini Hospital, Cesena, ItalyMaria Concetta Fargnoli - Department of Dermatology, University of L'Aquila, L'Aquila, ItalyPaola Ghiorzo - 1] Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. 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, ItalyBrigitte Bressac-de Paillerets - Service de Génétique, Gustave Roussy, Villejuif, FranceEduardo Nagore - 1] Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain. Department of Dermatology, Universidad Católica de Valencia, Valencia, SpainMarie Francoise Avril - Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, FranceNeil E Caporaso - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAMary L McMaster - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAMichael Cullen - 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. Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USAZhaoming Wang - 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. Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USAXijun Zhang - 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. Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USAWilliam Bruno - 1] Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. 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, ItalyLorenza Pastorino - 1] Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. 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, ItalyPaola Queirolo - 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, ItalyJose Banuls-Roca - Department of Dermatology, Hospital General Universitario de Alicante, Alicante, SpainZaida Garcia-Casado - Laboratory of Molecular Biology, Instituto Valenciano de Oncología, Valencia, SpainAmaury Vaysse - 1] INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, FranceHamida Mohamdi - 1] INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, FranceYasser Riazalhosseini - 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. Department of Human Genetics, McGill University, Montreal, Quebec, CanadaMario Foglio - SAS Quantome, Paris, FranceFanélie Jouenne - Service de Génétique, Gustave Roussy, Villejuif, FranceXing Hua - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAPaula L Hyland - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAJinhu Yin - Laboratory of Molecular Gerontology, National Institute on Aging, US National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USAHaritha Vallabhaneni - Laboratory of Molecular Gerontology, National Institute on Aging, US National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USAWeihang Chai - Section of Medical Sciences, School of Molecular Biosciences, Washington State University, Spokane, Washington, USAPaola Minghetti - Department of Dermatology, Maurizio Bufalini Hospital, Cesena, ItalyCristina Pellegrini - Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalySarangan Ravichandran - SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Simulation, Analysis and Mathematical Modeling Group, Advanced Biomedical Computing Center, Frederick, Maryland, USAAlexander Eggermont - 1] Service de Génétique, Gustave Roussy, Villejuif, France. Université Paris-Sud, Kremlin Bicêtre France, Gustave Roussy, Villejuif, FranceMark Lathrop - 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, FranceKetty Peris - Department of Dermatology, University of L'Aquila, L'Aquila, ItalyGiovanna Bianchi Scarra - Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, ItalyGiorgio Landi - Department of Dermatology, Maurizio Bufalini Hospital, Cesena, ItalyJi He - 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. Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USAJoshua N Sampson - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USASharon A Savage - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAMeredith Yeager - 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. Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USALynn R Goldin - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAFlorence Demenais - 1] INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France. Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, FranceStephen J Chanock - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAMargaret A Tucker - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAAlisa M Goldstein - Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USAYie Liu - National Institute on AgingMaria Teresa Landi - 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.
- Publication Details
- Nature genetics, Vol.46(5), pp.482-486
- Academic Unit
- Elson S. Floyd College of Medicine
- Publisher
- United States
- Grant note
- Z01 CP004410-31 / Intramural NIH HHS HHSN261200800001E / PHS HHS
- Identifiers
- 99900546745601842
- Language
- English
- Resource Type
- Accepted manuscript