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DNA-methyltransferase (DNMT)-3A which contains  DNMT3A1  and  DNMT3A2  isoforms have been suggested to play a crucial role in carcinogenesis and showed aberrant expression in most cancers. Accumulated evidences also indicated that single nucleotide polymorphisms (SNP) in DNMT genes were associated with susceptibility to different tumors. We hypothesized that genetic variants in  DNMT3A1  promoter region are associated with gastric cancer risk. We selected the tagSNPs from the HapMap database for the Chinese and genotyped in a case-control study to evaluate the association with gastric cancer (GC) in a Chinese population. We identified that the functional tagSNP rs7560488 T>C associated with a significantly increased risk of GC.  In vitro  functional analysis by luciferase reporter assay and EMSA indicated that the tagSNP rs7560488 T>C substantially altered transcriptional activity of  DNMT3A1  gene via influencing the binding of some transcriptional factors, although a definite transcriptional factor remains to be established. Compared with TT homozygotes, subjects who were TC heterozygotes and CC homozygotes exhibited a reduced expression of  DNMT3A1 . Furthermore, stratified analysis showed that individuals who harbor TC or CC genotypes less than 60 years old were more susceptible to GC. Our results suggest that the genetic variations in the  DNMT3A1  promoter contribute to the susceptibility to GC and also provide an insight that tagSNP rs7560488 T>C may be a promising biomarker for predicting GC genetic susceptibility and a valuable information in GC pathogenesis.

A Novel Functional TagSNP Rs7560488 in the DNMT3A1 Promoter Is Associated with Susceptibility to Gastric Cancer by Modulating Promoter Activity