Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
24686849
TITLE
POT1 loss-of-function variants predispose to familial melanoma.
ABSTRACT
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.
DATE PUBLISHED
2014 May
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2013/05/29
accepted 2014/03/07
aheadofprint 2014/03/30
entrez 2014/04/02 06:00
pubmed 2014/04/02 06:00
medline 2014/06/17 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Robles-Espinoza CD Robles-Espinoza Carla Daniela CD 1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. [2].
Harland M Harland Mark M 1] Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. [2].
Ramsay AJ Ramsay Andrew J AJ 1] Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain. [2].
Aoude LG Aoude Lauren G LG 1] Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia. [2].
Quesada V Quesada Víctor V Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
Ding Z Ding Zhihao Z Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Pooley KA Pooley Karen A KA Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Pritchard AL Pritchard Antonia L AL Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Tiffen JC Tiffen Jessamy C JC Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Petljak M Petljak Mia M Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Palmer JM Palmer Jane M JM Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Symmons J Symmons Judith J Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Johansson P Johansson Peter P Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Stark MS Stark Mitchell S MS Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Gartside MG Gartside Michael G MG Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Snowden H Snowden Helen H Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Montgomery GW Montgomery Grant W GW Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Martin NG Martin Nicholas G NG Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.
Liu JZ Liu Jimmy Z JZ Statistical Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Choi J Choi Jiyeon J Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, USA.
Makowski M Makowski Matthew M Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, USA.
Brown KM Brown Kevin M KM Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, USA.
Dunning AM Dunning Alison M AM Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Keane TM Keane Thomas M TM Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
López-Otín C López-Otín Carlos C Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
Gruis NA Gruis Nelleke A NA Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
Hayward NK Hayward Nicholas K NK 1] Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia. [2].
Bishop DT Bishop D Timothy DT 1] Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. [2].
Newton-Bishop JA Newton-Bishop Julia A JA 1] Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. [2].
Adams DJ Adams David J DJ 1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. [2].
INVESTIGATORS
JOURNAL
VOLUME: 46
ISSUE: 5
TITLE: Nature genetics
ISOABBREVIATION: Nat. Genet.
YEAR: 2014
MONTH: May
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1718
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Genet
COUNTRY: United States
ISSNLINKING: 1061-4036
NLMUNIQUEID: 9216904
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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CommentIn Clin Genet. 2014 Sep;86(3):217-8 24784786
GRANTS
GRANTID AGENCY COUNTRY
10589 Cancer Research UK United Kingdom
13031 Cancer Research UK United Kingdom
A10123 Cancer Research UK United Kingdom
C1287/A9540 Cancer Research UK United Kingdom
C588/A10589 Cancer Research UK United Kingdom
C588/A4994 Cancer Research UK United Kingdom
C8197/A10123 Cancer Research UK United Kingdom
WT091310 Wellcome Trust United Kingdom
WT098051 Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Amino Acid Sequence
Australia
Base Sequence
Genetic Predisposition to Disease genetics
Great Britain genetics
Humans genetics
Melanoma genetics
Models, Molecular genetics
Molecular Sequence Data genetics
Netherlands genetics
Pedigree genetics
Protein Binding genetics
Reverse Transcriptase Polymerase Chain Reaction genetics
Sequence Alignment genetics
Sequence Analysis, DNA genetics
Telomere metabolism
Telomere-Binding Proteins metabolism
SUPPLEMENTARY MESH
SUPPLMESHNAME SUPPLMESHTYPE
Melanoma, Cutaneous Malignant Disease
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 POT1 protein, human
0 Telomere-Binding Proteins
OTHER ID's
OTHERID SOURCE
EMS57346 NLM
PMC4266105 NLM
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