MTHFR c.677C>T Inhibits Cell Proliferation and Decreases Prostate Cancer Susceptibility in the Han Chinese Population in Shanghai.

Jun-Long Wu,Yuan-Yuan Qu,Ding-Wei Ye,Shu-Xian Zhou,Xuan Zhang,Rui Zhao,Cheng-Yuan Gu,Hai-Liang Zhang,Jian-Yuan Zhao,Yao Zhu,Hua-Lei Gan,Guo-Hai Shi,Kun Chang,Bo Dai

doi:10.1038/srep36290

Abstract

Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67–0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55–0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis.

Highlights

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of cancer death worldwide among men, and remains the first frequently diagnosed cancer in more developed countries[1]
We performed a large-scale, hospital-based, case-controlled study in Han Chinese men native to Shanghai to determine whether methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C were associated with prostate cancer (PCa) risk
We found that both heterozygous CT genotype and homozygous TT genotype carriers of rs1801133 had a significantly lower risk of developing PCa compared with those carrying wild-type CC genotype, which is in agreement with previous studies performed in Taiwanese patients[25] and the Liaoning Province[28]

Summary

Introduction

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of cancer death worldwide among men, and remains the first frequently diagnosed cancer in more developed countries[1]. The MTHFR gene has been identified to possess 98 different variants with benign, pathogenic or unknown significance which are listed on ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/). 677C>T) and rs1801131 (c.1298A>C) are two most extensively reported polymorphisms with a global minor allele frequency (GMAP) 0.245 and 0.249, respectively[19,20] These two variants have shown to be associated with the risk of PCa, somewhat conflicting results have been reported[21,22,23,24]. There was a limited sample size in the previous study regarding MTFHR variants in Han Chinese PCa susceptibility; and more importantly, this association has not been surveyed in Shanghai city, which had the highest PCa incidence in China. The current study aimed to investigate the association between these two common variants of MTHFR and PCa risk in a large-scale, hospital-based, case-control cohort in Shanghai city and to explore the underlying molecular mechanisms

Objectives

Methods

Results

Conclusion