Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA.
Cancer. 2012 Dec 1;118(23):5912-9. doi: 10.1002/cncr.27621. Epub 2012 May 30.
The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.
The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine-to-thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19-base-pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board-approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction-based genotyping of rs1801133 and rs70991108.
The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89-7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32-5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.
Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.
单侧视网膜母细胞瘤的发病率在全球范围内存在差异，这表明疾病的发生可能与环境因素有关。母亲在怀孕期间从蔬菜中摄取天然叶酸与后代患视网膜母细胞瘤的风险呈负相关。
作者采用病例对照研究设计，研究了视网膜母细胞瘤风险与叶酸代谢基因亚甲基四氢叶酸还原酶（MTHFR）（核苷酸 677 处胞嘧啶到胸腺嘧啶的替换 [MTHFR677C→T]；参考单核苷酸多态性 rs1801133）和二氢叶酸还原酶（DHFR）（内含子 1a 中 19 个碱基对缺失 [DHFR19bpdel]；rs70991108）中母体变异之间的关联。在墨西哥中部，研究人员招募了 103 名患有新诊断单侧视网膜母细胞瘤的儿童的母亲，以及 97 名有健康儿童的母亲，进行了一项机构审查委员会批准的研究。母亲接受了围产期特征的访谈，包括使用产前维生素补充剂，并提供外周血样本，用于基于聚合酶链反应的 rs1801133 和 rs70991108 的基因分型。
单侧视网膜母细胞瘤患儿母亲的 DHFR19bpdel 纯合子与患病风险相关（比值比，3.78；95%置信区间，1.89-7.55；P=0.0002），即使在控制了儿童的 DHFR19bpdel 基因型后（比值比，2.81；95%置信区间，1.32-5.99；P=0.0073）。在有 167 名母亲的亚组中，这些母亲的数据包括含有叶酸（叶酸的合成形式）的补充剂的产前摄入量，仅在报告服用叶酸补充剂的母亲中，DHFR19bpdel 相关的风险显著升高。母亲的 MTHFR 基因型与视网膜母细胞瘤的发病风险无关。
DHFR 基因中合成叶酸转化为生物叶酸所必需的多态性纯合子与视网膜母细胞瘤风险增加有关。在具有遗传易感性的人群亚组中，产前摄入合成叶酸补充剂可能与儿童早期致癌作用的风险增加有关。
