Folate Deficiency, Metabolism & Sporadic Retinoblastoma

描述(申请人提供)：这项研究的目的是检查调节叶酸代谢的母婴基因突变是否与发生散发性视网膜母细胞瘤的风险增加有关。与恶劣生活条件相关的环境因素可能会增加肿瘤形成的风险，因为在世界上几个不太富裕的地区，单侧视网膜母细胞瘤的发病率更高。视网膜母细胞瘤基因RB1在生发或分裂的视网膜细胞中的突变会导致肿瘤的发生。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。叶酸是一种甲基转移的调节剂，通常在神经组织中存在较高浓度，其缺乏可通过损害甲基转移和嘧啶的合成而导致突变。在怀孕期间不服用维生素补充剂和较少摄入含有叶酸的食物的妇女，生下患有视网膜母细胞瘤的孩子的风险会增加。亚甲基四氢叶酸还原酶(MTHFR)基因的C677T和A1298C突变以及蛋氨酸合成酶(MTRR)基因的A66G突变是叶酸代谢酶基因的常见突变，导致酶功能低下。这些与低叶酸和联合巴拉明(B12)摄入协同作用，增加神经管缺陷的风险。我们推测，由于叶酸摄入不足，加上视网膜形成的关键时期、子宫内和早期婴儿的MTHFR和MTRR酶功能降低，将导致散发性视网膜母细胞瘤的发生。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来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强化叶酸的食物，另一个在纽约，那里广泛食用叶酸强化食品，以确定散发性单侧视网膜母细胞瘤儿童及其母亲是否有更高的MTHFR和MTRR突变频率。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水平。如果我们的结果如预期的那样，该项目可能会为那些散发性视网膜母细胞瘤发病率较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.