Open AccessFunctional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population
Author(s) -
Yuan Qu,
Shu Zhou,
Xuan Zhang,
Rui Zhao,
Cheng Gu,
Kun Chang,
Xiao Yang,
Hua Gan,
Bo Dai,
Hai Liang Zhang,
Guanghua Shi,
Yao Zhu,
Ding Wei Ye,
Jian Zhao
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep36264
Subject(s) - prostate cancer , carcinogenesis , genotype , dna methylation , biology , methylation , homocysteine , genetics , gene , methyltransferase , cancer , cancer research , gene expression , endocrinology
Aberrant DNA methylation has been implicated in prostate carcinogenesis. The one-carbon metabolism pathway and related metabolites determine cellular DNA methylation and thus is thought to play a pivotal role in PCa occurrence. This study aimed to investigate the contribution of genetic variants in one-carbon metabolism genes to prostate cancer (PCa) risk and the underlying biological mechanisms. In this hospital-based case-control study of 1817 PCa cases and 2026 cancer-free controls, we genotyped six polymorphisms in three one-carbon metabolism genes and assessed their association with the risk of PCa. We found two noncoding MTR variants, rs28372871 T > G and rs1131450 G > A, were independently associated with a significantly increased risk of PCa. The rs28372871 GG genotype (adjusted OR = 1.40, P = 0.004) and rs1131450 AA genotype (adjusted OR = 1.64, P = 0.007) exhibited 1.40-fold and 1.64-fold higher risk of PCa, respectively, compared with their respective homozygous wild-type genotypes. Further functional analyses revealed these two variants contribute to reducing MTR expression, elevating homocysteine and SAH levels, reducing methionine and SAM levels, increasing SAH/SAM ratio, and promoting the invasion of PCa cells in vitro . Collectively, our data suggest regulatory variants of the MTR gene significantly increase the PCa risk via decreasing methylation potential. These findings provide a novel molecular mechanism for the prostate carcinogenesis.