Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Genet. 2014 May;46(5):482-6. doi: 10.1038/ng.2941. Epub 2014 Mar 30.

Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.

Author information

1
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].
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
3
Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
4
Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
5
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.
6
Service de Génétique, Gustave Roussy, Villejuif, France.
7
1] Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain. [2] Department of Dermatology, Universidad Católica de Valencia, Valencia, Spain.
8
Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France.
9
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] Cancer Genomics Research Laboratory, NCI-Frederick, SAIC-Frederick, Inc., Frederick, Maryland, USA.
10
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.
11
Department of Dermatology, Hospital General Universitario de Alicante, Alicante, Spain.
12
Laboratory of Molecular Biology, Instituto Valenciano de Oncología, Valencia, Spain.
13
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.
14
1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
15
SAS Quantome, Paris, France.
16
Laboratory of Molecular Gerontology, National Institute on Aging, US National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USA.
17
Section of Medical Sciences, School of Molecular Biosciences, Washington State University, Spokane, Washington, USA.
18
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
19
SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Simulation, Analysis and Mathematical Modeling Group, Advanced Biomedical Computing Center, Frederick, Maryland, USA.
20
1] Service de Génétique, Gustave Roussy, Villejuif, France. [2] Université Paris-Sud, Kremlin Bicêtre France, Gustave Roussy, Villejuif, France.
21
1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3] Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.
22
Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.

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.

PMID:
24686846
PMCID:
PMC4056593
DOI:
10.1038/ng.2941
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center