Identification of a melanoma susceptibility locus and somatic mutation in TET2.

Carcinogenesis

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

Published: September 2014

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146422PMC
http://dx.doi.org/10.1093/carcin/bgu140DOI Listing

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