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.
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Carla Daniela
authors.initials: CD
authors.lastname: Robles-Espinoza
authors.affiliation: Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ramsay
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Quesada
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Pooley
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Antonia L
authors.initials: AL
authors.lastname: Pritchard
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Jessamy C
authors.initials: JC
authors.lastname: Tiffen
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Mia
authors.initials: M
authors.lastname: Petljak
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Symmons
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Stark
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gartside
authors.affiliation: Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Snowden
authors.affiliation: Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Statistical Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Liu
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Makowski
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keane
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Newton-Bishop
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D001315:Australia; D001483:Base Sequence; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009426:Netherlands; D010375:Pedigree; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D000089804:Shelterin Complex; D012878:Skin Neoplasms; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006113:United Kingdom; D000096142:Cutaneous Malignant Melanoma
chemical_list: C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins