Folate Deficiency, Metabolism & Sporadic Retinoblastoma

描述（由申请人提供）：本研究的目的是检查母亲和婴儿叶酸代谢调控基因突变是否与散发性视网膜母细胞瘤发生风险增加相关。与不良生活条件相关的环境因素可能会增加肿瘤形成的风险，因为单侧视网膜母细胞瘤的发病率在世界上几个不太富裕的地区较高。视网膜母细胞瘤基因突变，视网膜母细胞瘤或分裂的视网膜细胞中的RB1导致肿瘤发展。大多数突变发生在甲基化胞嘧啶，这表明甲基转移异常可能导致诱变。叶酸是甲基转移的调节剂，通常在神经组织中以高浓度存在，其缺乏可通过受损的甲基转移和嘧啶合成导致诱变。在怀孕期间不服用产前维生素补充剂和摄入较少含叶酸食物的妇女，患视网膜母细胞瘤的风险增加。亚甲基四氢叶酸还原酶（MTHFR）基因中的C677 T和A1298 C突变以及甲硫氨酸合成酶（MTRR）基因中的A66 G突变是叶酸代谢酶基因中的常见突变，其导致功能较低的酶。这些与低叶酸和维生素B12摄入量协同作用，增加神经管缺陷的风险。 我们推测，由于摄入量不足，叶酸的可用性降低，加上在视网膜形成的关键时期，子宫内和婴儿早期功能较弱的MTHFR和MTRR酶，将导致散发性视网膜母细胞瘤的发展。这项分子流行病学研究建议使用病例对照设计，使用问卷和血液样本，检查两个母亲和儿童群体，一个在墨西哥中部，其饮食依赖于未强化叶酸的食物，另一个在纽约，其中叶酸强化食品被广泛消费，以确定散发性单侧视网膜母细胞瘤患儿及其母亲是否具有这些MTHFR和MTRR突变的增加频率。这项研究还将检查增加的风险是否取决于叶酸摄入量，红细胞和血浆叶酸水平以及血浆同型半胱氨酸。如果我们的结果如预期的那样，该项目可能会导致为散发性视网膜母细胞瘤发病率升高的人群制定新的预防策略。

DESCRIPTION (provided by applicant): The objective of this study is to examine whether mutations in maternal and infant genes regulating folate metabolism are associated with an increased risk for the development of sporadic retinoblastoma. Environmental factors associated with poor living conditions may increase the risk of tumor formation, as the incidence of unilateral retinoblastoma is higher in several less affluent regions of the world. Mutations in the retinoblastoma gene, RB1 in germinal or dividing retinal cells result in tumor development. Most mutations occur at methylated cytosines, suggesting that abnormalities in methyl transfer may lead to mutagenesis. Folate, a regulator of methyl group transfer, is normally found in high concentrations in neural tissues and its deficiency can lead to mutagenesis through impaired methyl group transfer and pyrimidine synthesis. Risk for having a child with retinoblastoma is increased in women who do not take prenatal vitamin supplements and consume fewer folate-containing foods during pregnancy. The C677T and A1298C mutations in the methylene tetrahydrofolate reductase (MTHFR) gene and the A66G mutation in the methionine synthetase (MTRR) gene are common mutations in folate metabolizing enzymes genes which result in less functional enzymes. These act synergistically with low folate and co-balamin (B12) intake and increase the risk for neural tube defects. We hypothesize that decreased folate availability, because of poor intake, combined with less functional MTHFR and MTRR enzymes during key periods of retinal formation, in utero and in early infancy will lead to development of sporadic retinoblastoma. This molecular epidemiologic study proposes to use a case-control design, using questionnaires and blood samples, to examine two populations of mothers and children, one in central Mexico whose diet relies on foods not fortified with folate, and one in New York, where folate-fortified foods are widely consumed, in order to determine whether children with sporadic unilateral retinoblastoma and their mothers have an increased frequency of these MTHFR and MTRR mutations. The study will also examine whether the increased risk varies depending on folate intake, and levels of red blood cell and plasma folate, and plasma homocysteine. If our results are as anticipated, this project may lead to the development of new preventive strategies for those populations with an elevated incidence of sporadic retinoblastoma.