Folate Deficiency, Metabolism & Sporadic Retinoblastoma

描述（由申请人提供）：本研究的目的是研究母体和婴儿调节叶酸代谢的基因突变是否与散发性视网膜母细胞瘤发生风险增加有关。与恶劣的生活条件相关的环境因素可能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一些不太富裕的地区较高。视网膜母细胞瘤基因RB1在萌发或分裂视网膜细胞中的突变导致肿瘤的发展。大多数突变发生在甲基化的胞嘧啶上，这表明甲基转移的异常可能导致突变。叶酸是甲基转移的调节剂，通常在神经组织中存在高浓度，缺乏叶酸可通过甲基转移和嘧啶合成受损导致突变。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，其孩子患视网膜母细胞瘤的风险会增加。亚甲基四氢叶酸还原酶（MTHFR）基因的C677T和A1298C突变和蛋氨酸合成酶（MTRR）基因的A66G突变是叶酸代谢酶基因中常见的突变，导致酶的功能降低。这些与低叶酸和维生素B12摄入协同作用，增加神经管缺陷的风险。我们推测，在视网膜形成的关键时期，在子宫和婴儿早期，叶酸摄入不足导致叶酸可用性降低，再加上MTHFR和MTRR酶功能降低，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采用病例对照设计，使用问卷调查和血液样本，检查两个母亲和儿童群体，一个在墨西哥中部，他们的饮食依赖于不添加叶酸的食物，另一个在纽约，叶酸强化食品被广泛食用，以确定散发性单侧视网膜母细胞瘤的儿童及其母亲是否增加了这些MTHFR和MTRR突变的频率。该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水平。如果我们的结果如预期的那样，这个项目可能会导致对那些散发性视网膜母细胞瘤发病率升高的人群开发新的预防策略。

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.