Unmetabolized folic acid and retinoblastoma.

描述(由申请人提供)：单侧视网膜母细胞瘤(RTB)的发病率因地域而异(1)。在美国，拉美裔儿童的发病率最高(2)。对其病因知之甚少。诊断单侧RTB的中位年龄为23个月，这表明肿瘤的发生始于胎儿发育或婴儿期。在我们在墨西哥中部进行的病例对照研究中，我们假设母亲叶酸的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，二氢叶酸还原酶(DHFR)基因(DHFR19bpdel/del)内含子-1a缺失19个碱基对(BP)的母亲预测生下的孩子患有单侧RTB，在怀孕早期服用叶酸补充剂的母亲风险更大。DHFR是还原叶酸并将其转化为四氢叶酸的关键。生理性叶酸天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 和维生素补充剂。在由老年人组成的Framingham队列中，携带DHFR19bpdel/del的参与者循环非代谢叶酸(CUMFA)水平升高的风险增加，特别是当每天叶酸摄入量超过500微克(3，4)时。这一阈值远低于允许的上限(UL)，也低于孕妇的膳食参考摄入量(DRI)(5)。携带DHFR19bpdel/del的女性患乳腺癌的风险增加，但仅限于服用维生素补充剂的女性(6)。在我们的研究中，母亲接受了有效的食物频率问卷(FFQ)的采访，以记录当前和产前的饮食和补充摄入量(7，8)。墨西哥于2000年底开始强制使用叶酸强化小麦面粉(9)；然而，墨西哥现有的营养含量表没有考虑强化小麦面粉中的叶酸。因此，我们的研究母亲没有关于叶酸总摄入量的数据。我们假设，我们发现的与母体DHFR19bpdel/del相关的风险增加是通过母体cUMFA水平来调节的。我们认为，RTB病例的母亲比对照组的母亲更有可能升高cUMFA。此外，我们假设患有DHFR19bpdel/del的母亲在从强化食品和补充剂中摄入叶酸适度增加时，cUMFA水平会更高。我们建议1)测量167名患有单侧RTB和150名对照儿童的母亲的储存样本中的cUMFA，以检查与DHFR19bpdel/del相关的视网膜母细胞瘤的风险是否与cUMFA相关；以及2)更新我们的墨西哥营养成分表，以考虑叶酸强化，以便使用已经从FFQ获得的数据来计算我们的种马母亲的合成叶酸的母亲摄入量。我们将检验母亲的cUMFA水平是否可以通过叶酸的总摄入量来预测，以及这种关联是否会因DHFR基因而异。我们建议的研究是第一次研究儿童肿瘤的风险与cUMFA的积聚和母亲摄入的叶酸减少受损有关。我们的研究结果可能会对公共政策和我们对儿童癌症发生的理解产生重大影响。

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.