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 Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
Carcinogenesis. 2014 Sep;35(9):2097-101. doi: 10.1093/carcin/bgu140. Epub 2014 Jun 30.
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.
尽管遗传研究已经报道了许多与黑色素瘤风险相关的基因座，但该疾病的复杂遗传结构尚未完全被理解。我们试图通过全基因组关联研究（GWAS）鉴定与黑色素瘤风险相关的常见遗传变异，该研究纳入了 2298 例病例和 6654 例对照。15 个已知基因座中的 13 个在名义上具有显著性。共选择了 69 个单核苷酸多态性（SNP）进行 2 个独立的黑色素瘤 GWAS 数据集（共 5149 例病例和 12795 例对照）的计算机复制。有 7 个新的 SNP 在黑色素瘤风险方面具有名义上的显著性关联。这 7 个 SNP 进一步在 234 例黑色素瘤病例和 238 例对照中进行了基因分型。SNP rs4698934 与黑色素瘤风险呈名义显著相关。每个 T 等位基因的联合优势比=1.18；95%置信区间（1.10-1.25）；合并 P=7.70×10(-7)。该 SNP 位于染色体 4q24 上的 TET2 基因内含子中。此外，通过下一代测序在 22 例散发性黑色素瘤病例中的 1 例中鉴定出 TET2 的新型体细胞突变。TET2 编码 TET 家族酶的成员，该酶将 5-甲基胞嘧啶氧化为 5-羟甲基胞嘧啶（5hmC）。正如我们之前报道的那样，TET2 是黑色素瘤的潜在表观遗传生物标志物，观察到 TET2 转录表达降低。这项研究首次表明 TET2 遗传变异和突变与黑色素瘤有关。
