Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population

• Published in: Scientific reports 2016-11, Vol.6 (1), p.36264, Article 36264
• Main Authors: Qu, Yuan-Yuan, Zhou, Shu-Xian, Zhang, Xuan, Zhao, Rui, Gu, Cheng-Yuan, Chang, Kun, Yang, Xiao-Qun, Gan, Hua-Lei, Dai, Bo, Zhang, Hai-Liang, Shi, Guo-Hai, Zhu, Yao, Ye, Ding-Wei, Zhao, Jian-Yuan
• Format: Article
• Language: English
• Subjects: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - genetics; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - metabolism; 692/4025/2768/1753/466; 692/4028/67/589/466; Aged; Carbon; Carcinogenesis; Case-Control Studies; DNA methylation; Gene Frequency; Genes; Genetic Predisposition to Disease - genetics; Genotype; Homocysteine; Humanities and Social Sciences; Humans; Male; Metabolism; Metabolites; Methionine; Methyltransferase; Middle Aged; MTR gene; multidisciplinary; Polymorphism, Single Nucleotide; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Risk Factors; Science
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep36264

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.