Identification of a melanoma susceptibility locus and somatic mutation in TET2

Fengju Song; Christopher I Amos; Jeffrey E Lee; Christine G Lian; Shenying Fang; Hongliang Liu; Stuart MacGregor; Mark M Iles; Matthew H Law; Neal I Lindeman; Grant W Montgomery; David L Duffy; Anne E Cust; Mark A Jenkins; David C Whiteman; Richard F Kefford; Graham G Giles; Bruce K Armstrong; Joanne F Aitken; John L Hopper; Kevin M Brown; Nicholas G Martin; Graham J Mann; D Timothy Bishop; Julia A Newton Bishop; GenoMEL consortium; Peter Kraft; Abrar A Qureshi; Peter A Kanetsky; Nicholas K Hayward; David J Hunter; Qingyi Wei; Jiali Han

doi:10.1093/carcin/bgu140

Identification of a melanoma susceptibility locus and somatic mutation in TET2

Carcinogenesis. 2014 Sep;35(9):2097-101. doi: 10.1093/carcin/bgu140. Epub 2014 Jun 30.

Authors

Fengju Song¹, Christopher I Amos², Jeffrey E Lee³, Christine G Lian⁴, Shenying Fang³, Hongliang Liu⁵, Stuart MacGregor⁶, Mark M Iles⁷, Matthew H Law⁶, Neal I Lindeman⁴, Grant W Montgomery⁶, David L Duffy⁶, Anne E Cust⁸, Mark A Jenkins⁹, David C Whiteman⁶, Richard F Kefford¹⁰, Graham G Giles¹¹, Bruce K Armstrong¹², Joanne F Aitken¹³, John L Hopper⁹, Kevin M Brown¹⁴, Nicholas G Martin⁶, Graham J Mann¹⁰, D Timothy Bishop⁷, Julia A Newton Bishop⁷; GenoMEL consortium; Peter Kraft¹⁵, Abrar A Qureshi¹⁶, Peter A Kanetsky¹⁷, Nicholas K Hayward¹⁸, David J Hunter¹⁵, Qingyi Wei¹⁹, Jiali Han²⁰

Affiliations

¹ 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.
² Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
³ Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁶ Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
⁷ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
⁸ 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.
⁹ Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Victoria 3052, Australia.
¹⁰ Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead, New South Wales 2145, Australia.
¹¹ Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria 3053, Australia.
¹² Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, New South Wales 2006, Australia.
¹³ Viertel Centre for Research in Cancer Control, Cancer Council Queensland, Brisbane, Queensland 4004, Australia.
¹⁴ Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA.
¹⁵ Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
¹⁶ Channing Division of Network Medicine and Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁷ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁸ Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
¹⁹ Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA, [email protected] [email protected].
²⁰ 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 [email protected].

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural

MeSH terms

Case-Control Studies
DNA-Binding Proteins / genetics*
Dioxygenases
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Melanoma / genetics*
Mutation
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins / genetics*
Risk Factors
Skin Neoplasms / genetics*

Substances

DNA-Binding Proteins
Proto-Oncogene Proteins
Dioxygenases
TET2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding