Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population.
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.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yuan-Yuan
YY
Qu
The State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics &Development, School of Life Sciences, Fudan University, Shanghai 200433, China.|Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Shu-Xian
SX
Zhou
The State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics &Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
Xuan
X
Zhang
The State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics &Development, School of Life Sciences, Fudan University, Shanghai 200433, China.|Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Rui
R
Zhao
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cheng-Yuan
CY
Gu
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Kun
K
Chang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Xiao-Qun
XQ
Yang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Hua-Lei
HL
Gan
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Bo
B
Dai
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Hai-Liang
HL
Zhang
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Guo-Hai
GH
Shi
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yao
Y
Zhu
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Ding-Wei
DW
Ye
The State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics &Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
Jian-Yuan
JY
Zhao
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase