Abstract.Various studies have demonstrated that the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism contributes to the risk of prostate cancer, while other studies have provided conflicting findings. In the present study, we carried out a comprehensive meta-analysis with the aim of determining whether there is a significant association of the MTHFR gene A1298C polymorphism with the susceptibility of prostate cancer. Studies on the MTHFR gene A1298C polymorphism and prostate cancer were retrieved using the electronic PubMed database without any restriction on language through Aug 21, 2011. Data were abstracted by a standardized protocol. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association. IntroductionProstate cancer (PC) is the most common malignancy and the second leading cause of cancer-related death in men in industrialized countries (1,2). Its incidence is at a relatively low rate in the Asian population (3), but is increasing rapidly (4). It is supposed that complex elements, such as hormones, age, family history of PC, cultural and enviromental factors and genetic background (3), contribute to the cancerization and progression of PC. However, the specific mechanism remains undetermined.Folate is indispensably required for DNA synthesis and methylation of DNA and histones. Epidemiological studies have shown an effective association between low folate intake and an increased cancer risk (5,6). MTHFR plays a vital role in the metabolism of folates by irreversibly converting 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate (7), which donates a methyl group for the remethylation of homocysteine to methionine used for DNA synthesis and repair (8). Therefore, MTHFR deficiency may lead to DNA hypomethylation to initialize cancerization and affect the progression of malignant tumors (9,10).The human MTHFR gene, composed of 11 exons, is located at chromosome 1p36.3, codes cDNA of 2.2-kb in length and produces a protein of 656 amino acids (11). The 1298A>C polymorphism, marked as rs1801131 in the NCBI database, is located at exon 7 and results in a glutamate-to-valine substitution at codon 429 (8). Alterations in genomic bases result in single-nucleotide polymorphisms (SNPs), which may subsequently affect the genetic instability, amino acid sequence and function of protein. Recently, SNPs have been used as a tool for predicting diseases (12) in addition to carcinogenesis (13,14). The MTHFR gene A1298C polymorphism has been implicated in several diseases (15,16), including various types of cancer (17,18), and has been investigated in relation to the risk of PC but with inconclusive results (19)(20)(21)(22)(23)(24)(25)(26)(27). Among the nine eligible casecontrol studies, three considered the MTHFR gene A1298C polymorphism as a genetic marker for PC (19,24,26), while six reported negative associations between the two (20)(21)(22)(23)25,27). Hence, we carried out a meta-analysis concerning the association between the MTHFR ge...