Unmetabolized folic acid and retinoblastoma.

描述（由申请人提供）：单侧视网膜母细胞瘤（Rtb）的发病率因地理位置而异（1）。在美国，拉丁裔儿童的发病率最高（2）。关于其病因学知之甚少。诊断单侧Rtb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。在墨西哥中部的病例对照研究中，我们假设母亲摄入叶酸和调节叶酸代谢的基因变异可能预测发病率。初步结果表明，母亲纯合性为19个碱基对（bp）缺失的内含子-1a的二氢叶酸还原酶（DHFR）基因（DHFR19bpdel/del）预测有一个孩子与单侧Rtb，和风险似乎更大的母亲谁采取叶酸补充剂在其妊娠的第一个三个月。DHFR对于减少叶酸并将其转化为四氢叶酸至关重要。生理叶酸是天然存在于一些蔬菜和其他食物，而叶酸是合成形式的强化食品中发现 和维生素补充剂。在由老年人组成的Frachial队列中，DHFR 19 bpdel/del参与者的循环未代谢叶酸（cUMFA）水平升高的风险增加，特别是当每日叶酸摄入量超过500微克时（3，4）。这一阈值远低于耐受上限（UL），也低于孕妇的膳食参考摄入量（DRI）（5）。DHFR19bp缺失/缺失的女性患乳腺癌的风险增加，但仅在服用维生素补充剂的人群中（6）。在我们的研究中，使用经过验证的食物频率问卷（FFQ）对母亲进行了采访，以获取当前和产前的饮食和补充剂摄入量（7，8）。墨西哥在2000年末开始强制性地在小麦粉中添加叶酸（9）;然而，墨西哥现有的营养素含量表没有考虑到强化小麦粉中的叶酸。因此，我们的研究母亲无法获得叶酸总摄入量的数据。我们推测，我们发现与母体DHFR19bpdel/del相关的风险增加是通过母体cUMFA水平介导的。我们认为，结核病病例的母亲比对照组的母亲更有可能有升高的cUMFA。此外，我们假设DHFR 19 bpdel/del的母亲从强化食品和补充剂中摄入叶酸适度升高时，cUMFA水平较高。我们建议：1）测量167名单侧Rtb儿童和150名对照儿童母亲的储存样本中的cUMFA，以检查与DHFR 19 bpdel/del相关的视网膜母细胞瘤风险是否与cUMFA相关; 2）更新墨西哥营养成分表，以说明叶酸强化，为了计算我们的种马母亲合成叶酸的摄入量，使用已经从FFQ获得的数据。我们将研究是否通过叶酸的总摄入量来预测母亲的cUMFA水平，以及这种关联是否随DHFR基因型而变化。我们提出的研究是第一个检查与cUMFA积累和母亲摄入叶酸减少受损相关的儿科肿瘤风险的研究。我们的研究结果可能会显着影响公共政策，以及我们对儿科癌症发生的理解。

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.