Unmetabolized folic acid and retinoblastoma.

描述（由申请人提供）：单侧视网膜母细胞瘤（Rtb）的发病率在地理上有所不同(1)。在美国，拉丁裔儿童的发病率最高(2)。其病因尚不清楚。单侧Rtb诊断的中位年龄为23个月，表明肿瘤发生始于胎儿发育或婴儿期。在我们墨西哥中部的病例对照研究中，我们假设母亲叶酸摄入量和调节叶酸代谢的基因变异可能预测发病率。初步结果显示，母亲二氢叶酸还原酶（DHFR）基因1a内含子缺失19个碱基对（bp）的纯合性（DHFR19bpdel/del）预示着孩子患有单侧Rtb，并且在怀孕前三个月服用叶酸补充剂的母亲患Rtb的风险更大。DHFR对于还原叶酸并将其转化为四氢叶酸至关重要。生理性叶酸自然存在于一些蔬菜和其他食物中，而叶酸是在强化食品中发现的合成形式

DESCRIPTION (provided by applicant): Incidence of unilateral retinoblastoma (Rtb) varies geographically(1). In the US, incidence is highest among Latino children(2). Little is known regarding its etiology. Median age for diagnosis of unilateral Rtb is 23 months, suggesting that tumor genesis begins during fetal development or infancy. In our case-control study in central Mexico, we hypothesized that maternal intake of folate and variations in genes regulating folate metabolism might predict incidence. Initial results show that maternal homozygosity for a 19 base pair (bp) deletion in intron-1a of the dihydrofolate reductase (DHFR) gene (DHFR19bpdel/del) predicts having a child with unilateral Rtb, and risk appears greater in mothers who took folic acid supplements in their 1st trimester of pregnancy. DHFR is critical for reducing folic acid and converting it into tetrahydrofolate. Physiologic folate is naturally occurrng in some vegetables and other foods, while folic acid is the synthetic form found in fortified foods and vitamin supplements. In the Framingham cohort, composed of older adults, participants with DHFR19bpdel/del are at an increased risk of having elevated levels of circulating unmetabolized folic acid (cUMFA), particularly when daily folic acid intake exceeds 500 micrograms(3,4). This threshold is well below the tolerated upper limit (UL) and is less than the Dietary Reference Intake (DRI) for pregnant women(5). Women with DHFR19bp del/del have an increased risk for breast cancer, but only among those taking vitamin supplements(6). Mothers in our study were interviewed using a validated Food Frequency Questionnaire (FFQ) to capture current and prenatal diet and supplement intake(7,8). Mexico began mandatory wheat flour fortification with folic acid in late 2000(9); however, existing nutrient content tables in Mexico do not account for folic acid from fortified wheat flour. Data on total folic acid intake is therefore not available fr our study mothers. We hypothesize that the increased risk we found associated with maternal DHFR19bpdel/del is mediated through maternal levels of cUMFA. We propose that mothers of Rtb cases are more likely to have elevated cUMFA than mothers of controls. In addition, we hypothesize that mothers with DHFR19bpdel/del will have higher levels of cUMFA when their intake of folic acid from fortified foods and supplements is moderately elevated. We propose 1) to measure cUMFA in stored samples from mothers of 167 children with unilateral Rtb and 150 controls in order to examine whether risk of retinoblastoma associated with DHFR19bpdel/del is associated with cUMFA; and 2) to update our Mexican nutrient composition tables to account for folic acid fortification, in order to calculate maternal intake of synthetic folic acid in our stud mothers using data already captured from the FFQ. We will examine whether levels of cUMFA in our mothers are predicted by total intake of folic acid, and whether this association varies wit DHFR genotype. Our proposed study is the first to examine risk of a pediatric tumor associated with accumulation of cUMFA and impaired maternal reduction of ingested folic acid. Results of our study could significantly affect both public policy, and our understanding of pediatric carcinogenesis.