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Relationship between Methylenetetrahydrofolate Reductase C677T and A1298C Genotypes and Haplotypes and Prostate Cancer Risk and Aggressiveness

¹ Department of Cancer Biology, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio; ² Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; ³ Department of Preventive Medicine, University of Southern California, Los Angeles, California; and ⁴ Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, California

Requests for reprints: John S. Witte, Department of Epidemiology and Biostatistics, University of California-San Francisco, 500 Parnassus Avenue, MU-420 West, San Francisco, CA 94143-0560. Phone: 415-502-6882; Fax: 415-476-6014. E-mail: jwitte{at}itsa.ucsf.edu

Previous reports indicate that polymorphisms in the MTHFR gene play a role in cancer development, but their potential impact on prostate cancer has not been well studied. Here, we evaluate the association between two MTHFR polymorphisms, C677T and A1298C, and prostate cancer risk and aggressiveness in a moderately large family-based case-control study (439 cases and 479 sibling controls). Among all study subjects, we observed no association between the C677T variant and prostate cancer but a slight positive association between the A1298C variant and risk of this disease [odds ratio (OR) 1.41, 95% confidence interval (CI) 0.96-2.06; P = 0.08]. When stratifying the study population by disease aggressiveness at diagnosis, the C677T variant was positively associated with risk among men with less advanced disease (OR 1.86, 95% CI 1.00-3.46; P = 0.05). In contrast, when looking at men with more advanced disease, the C677T variant was inversely associated with risk (OR 0.51, 95% CI 0.32-0.82; P = 0.01), whereas the A1298C variant was positively associated with risk (OR 1.79, 95% CI 1.06-3.02; P = 0.03). Furthermore, the 677T-1298A haplotype was positively associated with prostate cancer among men with less advanced disease (OR 1.84, 95% CI 1.07-3.16; P = 0.03) and inversely associated with risk of more advanced disease (OR 0.47, 95% CI 0.29-0.76; P = 0.002). Our findings suggest that 677T and 1298A, or another variant on their haplotype, may be associated with a reduced risk of progression to more advanced prostate cancer.

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