title: Identification of a melanoma susceptibility locus and somatic mutation in TET2.
abstract: Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10(-) (7). This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.
authors: Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors: Fengju
authors: F
authors: Song
authors: Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
authors: Christopher I
authors: CI
authors: Amos
authors: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jeffrey E
authors: JE
authors: Lee
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Christine G
authors: CG
authors: Lian
authors: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Shenying
authors: S
authors: Fang
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors: Hongliang
authors: H
authors: Liu
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: Stuart
authors: S
authors: MacGregor
authors: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors: Mark M
authors: MM
authors: Iles
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: Matthew H
authors: MH
authors: Law
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Neal I
authors: NI
authors: Lindeman
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: Grant W
authors: GW
authors: Montgomery
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: David L
authors: DL
authors: Duffy
authors: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria 3052, Australia, Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Anne E
authors: AE
authors: Cust
authors: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors: Mark A
authors: MA
authors: Jenkins
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: David C
authors: DC
authors: Whiteman
authors: Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead, New South Wales 2145, Australia.
authors: Richard F
authors: RF
authors: Kefford
authors: Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria 3053, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Bruce K
authors: BK
authors: Armstrong
authors: Viertel Centre for Research in Cancer Control, Cancer Council Queensland, Brisbane, Queensland 4004, Australia.
authors: Joanne F
authors: JF
authors: Aitken
authors: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors: John L
authors: JL
authors: Hopper
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA.
authors: Kevin M
authors: KM
authors: Brown
authors: Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead, New South Wales 2145, Australia.
authors: Graham J
authors: GJ
authors: Mann
authors: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors: D Timothy
authors: DT
authors: Bishop
authors: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors: Julia A Newton
authors: JA
authors: Bishop
authors: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Peter
authors: P
authors: Kraft
authors: Channing Division of Network Medicine and Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Abrar A
authors: AA
authors: Qureshi
authors: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Peter A
authors: PA
authors: Kanetsky
authors: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
authors: Nicholas K
authors: NK
authors: Hayward
authors: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors: David J
authors: DJ
authors: Hunter
authors: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA, jialhan@iu.edu qingyi.wei@duke.edu.
authors: Qingyi
authors: Q
authors: Wei
authors: Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, Channing Division of Network Medicine and Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA, Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA and Department of Dermatology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA jialhan@iu.edu.
authors: Jiali
authors: J
authors: Han
mesh_terms: D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human