Nutrition and Cancer, 61(5), 617–628 Copyright © 2009, Taylor & Francis Group, LLC ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635580902846593 Folate Intake and Prostate Cancer Risk: A Case-Control Study Jackilen Shannon Oregon Health & Science Universityand Portland Veterans AffairsMedical Center, Portland, Oregon, USA Elena Phoutrides Oregon Health & Science University, Portland, Oregon, USA Amy Palma and Paige Farris Oregon Health & Science Universityand Portland Veterans AffairsMedical Center, Portland, Oregon, USA Laura Peters Portland Veterans Affairs Medical Center Portland, Oregon, USA Anna Forester and Carrie J. Tillotson Oregon Health & Science University, Portland, Oregon, USA Mark Garzotto Oregon Health & Science Universityand Portland Veterans AffairsMedical Center, Portland, Oregon, USA Folate deficiency has been implicated in the carcinogenesis of several tumor types. The role of folate in prostate cancer remains indeterminate. We investigated folate as a risk factor for prostate cancer among 140 biopsy-confirmed prostate cancer patients, 230 age-matched clinic controls, and 250 negative prostate biopsy con- trols. Dietary folate intake was inversely associated with overall risk of prostate cancer as compared to clinic controls ( P for a linear trend = 0.003). When stratified by disease severity, dietary folate and folate from natural sources were associated with reduced risk of high-grade cancer as compared to both clinic controls ( P for a linear trend = 0.0009 and 0.02, respectively) and biopsy neg- ative controls ( P for a linear trend = 0.03 and 0.05, respectively). There was no interaction between alcohol consumption and folate intake. These analyses support an inverse association between di- etary folate intake and prostate cancer risk and primarily risk of high-grade prostate cancer. Submitted 15 October 2008; accepted in final form 2 February 2009. Address correspondence to Jackilen Shannon, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (L606), Portland, OR 97239-3098. Phone: 503-494-4993. E-mail: shannoja@ohsu.edu INTRODUCTION Prostate cancer is a highly prevalent and deadly cancer among older men. As the most commonly diagnosed new cancer and the second most common cause of cancer deaths in men in the United States (1), it is important to consider modifiable lifestyle factors that can reduce the risk of prostate cancer. Although many major risk factors such as age and ethnicity are not modi- fiable, recent data suggests that risk may be decreased by diet (2). Folate is a micronutrient that is involved in one-carbon metabolism, a process that regulates many important biologic functions including nucleotide synthesis and deoxyribonucleic acid (DNA) methylation (3). DNA methylation is an important form of transcriptional control; both hypomethylation and hy- permethylation alter gene expression (4). Folate nutrition has been associated with changes in methylation status in a number of important genes involved in carcinogenesis (5). Additionally, folate deficiencies are suspected to be responsible for increased misincorporation of uracil into DNA, which can result in double- stranded DNA breaks (6). Proper folate nutrition helps promote DNA integrity, and as a result, it is suggested that folate defi- ciency could result in increased risk of several cancers such as colon cancer (7,8) and breast cancer (9–11). The association between prostate cancer risk and folate intake remains under study. In a cohort study of 964 men conducted 617