title: Germline TERT promoter mutations are rare in familial melanoma.
abstract: Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK. m.harland@leeds.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Mia
authors.initials: M
authors.lastname: Petljak
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Carla Daniela
authors.initials: CD
authors.lastname: Robles-Espinoza
authors.affiliation: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: van Doorn
authors.affiliation: Strangeways Research Laboratory, Departments of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, 2, Worts Causeway, Cambridge, CB1 8RN, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Pooley
authors.affiliation: Strangeways Research Laboratory, Departments of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, 2, Worts Causeway, Cambridge, CB1 8RN, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
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: Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Karin A W
authors.initials: KA
authors.lastname: Wadt
authors.affiliation: Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
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, Leeds 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, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK. D.T.Bishop@leeds.ac.uk.
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D012878:Skin Neoplasms; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: Familial; Genetic; Melanoma; Mutation; TERT