Folate and related micronutrients, folate-metabolising genes and risk of ovarian cancer

Background/Objective: Folates are essential for DNA synthesis and methylation, and thus may have a role in carcinogenesis. Limited evidence suggests folate-containing foods might protect against some cancers and may partially mitigate the increased risk of breast cancer associated with alcohol intake, but there is little information regarding ovarian cancer. Our aim was to evaluate the role of folate and related micronutrients, polymorphisms in key folate-metabolising genes and environmental factors in ovarian carcinogenesis. Subjects/Methods: Participants in the Australian Ovarian Cancer Study (1363 cases, 1414 controls) self-completed risk factor and food-frequency questionnaires. DNA samples (1638 cases, 1278 controls) were genotyped for 49 tag single-nucleotide polymorphisms (SNPs) in the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and MTR reductase (MTRR) genes. Logistic regression models were used to generate adjusted odds ratios and 95% confidence intervals. Results: We saw no overall association between the intake of folate, B vitamins or other methyl donors and ovarian cancer risk, although increasing folate from foods was associated with reduced risk among current smokers (P-trend = 0.03) and folic acid intake was associated with borderline significant increased risks among women who consumed >= 1 standard alcoholic drinks/day (odds ratio (OR) = 1.64; 95% confidence interval (CI) 1.05-2.54, P-trend = 0.05). Two SNPs (rs7365052, rs7526063) showed borderline significant inverse associations with ovarian cancer risk; both had very low minor allele frequencies. There was little evidence for interaction between genotype and micronutrient intake or for variation between different histological subtypes of ovarian cancer. Conclusions: Our data provide little evidence to support a protective role for folate in ovarian carcinogenesis but suggest further evaluation of the joint effects of folic acid and alcohol is warranted. European Journal of Clinical Nutrition (2011) 65, 1133-1140; doi: 10.1038/ejcn.2011.99; published online 1 June 2011