Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer C. Marchal a, * , M. Redondo b , A. Reyes-Engel c , E. Perea-Milla b , M.J. Gaitan c , J. Machuca a , F. Diaz d , J. Caballero e , J. Carnero a a Urology Department, Hospital Clı ´nico Universitario, Virgen de la Victoria, Campus de Teatinos s/n, Ma ´laga 29010, Spain b Research Unit, Hospital Costa del Sol, Marbella 29600, Spain c Biochemistry Department, Facultad de Medicina, Universidad de Ma ´laga, Campus de Teatinos s/n, Ma ´laga 29010, Spain d Urology Department, Hospital Carlos Haya, Avda. Carlos Haya, Malaga, Spain e Urology Department, Hospital Costa del Sol, Marbella 29600, Spain Accepted 14 September 2007 Available online 29 October 2007 Abstract Polymorphisms of the genes 5 0 -10 0 -methylenetetrahydrofolate reductase (MTHFR, 677CT and 1298AC ), methionine synthase (MTR, 2756AC ) and methionine synthase reductase (MTRR, 66AC ) provoke variations in enzyme activity, which can lead to alterations in the metabolism of folates and in the synthesis of S-adenosyl-methionine (SAM), the most active methyl donor in the body. This could play an important role in carcinogenesis through the degree of DNA methylation and of nucleotide synthesis. In the present study, four polymorphisms were studied, two of the methylenetetrahydrofolate reductase gene, and the other two of me- thionine synthase and methionine synthase reductase. Our aim was to study the association between prostate carcinoma susceptibility and these polymorphisms. A hospital-based caseecontrol study was conducted in 182 patients (mean age: 70.7  7.29 years) with histologically confirmed prostate carcinoma and in 205 control subjects (mean age: 70.3  7.82 years) diagnosed with benign prostatic hyperplasia (BPH). Genomic DNA was extracted from peripheral leukocytes. Comparison of the MTHFR CT and TT genotypes in patients and the controls revealed significant differences (0.57 vs 0.38) (OR: 2.19, 95% CI: 1.46e3.30) and (0.06 vs 0.15) (OR: 0.36, 95% CI: 0.17e0.73), respectively. No statistically significant differences were found between patients and controls with respect to the MTHFR 1298AC, the MTR 2756AC and the MTRR 66AC polymorphisms. However, among the patients, the MTR 2756 allele C was related to a high Gleason score. We conclude that the polymorphism MTHFR C677T is clearly related to prostatic carcinogenesis, on the contrary to the other polymor- phisms studied, although the MTR 2756 allele C acts as a factor of tumor aggressiveness, this being found in tumors with high carcinogenic potential. Ó 2007 Elsevier Ltd. All rights reserved. Key words: Prostate cancer; MTHFR; MTR; MTRR; Folate metabolism Introduction Promoter methylation plays an important role in the in- activation of tumor suppressor genes during tumorigenesis. Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA meth- ylation and nucleotide synthesis. Methylenetetrahydrofolate reductase (MTHFR) is a polymorphic enzyme involved in folate metabolism that catalyzes the conversion of 5 0 ,10 0 -methylenetetrahydrofo- late to 5-methyltetrahydrofolate; this serves as a methyl donor in the remethylation of homocysteine to methionine. Subjects with the mutant homozygous genotype 677TT have about 30% of the in vitro MTHFR enzyme activity of persons with the 677CC wild-type genotype, whereas heterozygotes (677CT ) have about 65% of normal enzyme activity. 1 Up to 15% of the population is homozygous for Abbreviations: MTHFR, methylenetetrahydrofolate reductase; MTR, methionine reductase; MTRR, methionine synthase reductase; BPH, benign prostatic hyperplasia; GSTP-1, glutathione S-transferase. * Corresponding author. Tel.: þ34 607405052; fax: þ34 951 298495. E-mail address: crmarchal@supercable.es (C. Marchal). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.09.008 Available online at www.sciencedirect.com EJSO 34 (2008) 805e810 www.ejso.com