Identification of a melanoma susceptibility locus and somatic mutation in TET2
Menée sur plusieurs cohortes de patients et de témoins, cette étude d'association sur le génome entier identifie un polymorphisme à simple nucléotide, situé dans le gène TET2 sur la région chromosomique 4q24, en association avec une susceptibilité au mélanome
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 2,298 cases and 6,654 controls. Thirteen out of fifteen known loci were replicated with nominal significance. A total of 69 SNPs were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5,149 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 one out 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.
http://carcin.oxfordjournals.org/content/early/2014/06/27/carcin.bgu140.abstract