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. HopperKevin M. Brown, Nicholas G. Martin, Graham J. Mann, D. Timothy Bishop, Julia A. Newton Bishop, Peter Kraft, Abrar A. Qureshi, Peter A. Kanetsky, Nicholas K. Hayward, David J. Hunter, Qingyi Wei, Jiali Han*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Article numberbgu140
Pages (from-to)2097-2101
Number of pages5
Issue number9
Publication statusPublished - Sep 2014
Externally publishedYes


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