Methylation and mutations in RB1 and variants of synthetic folic acid metabolism

RB1 的甲基化和突变以及合成叶酸代谢的变异

• 批准号: 9139422
• 负责人: Manuela A Orjuela
• 金额: $ 51.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139422
• 关键词: Adult; Affect; Age; Alleles; Biological; Biological Assay; Case Series; Cells; Child; Childhood; Colon Carcinoma; Colonic Adenoma; CpG Islands; Cytosine; DNA; Data; Deamination; Defect; Development; Diet; Dietary intake; Dihydrofolate Reductase; Disease; Environmental Exposure; Epidemiologic Studies; Evaluation; Fetal Development; First Pregnancy Trimester; Folic Acid; Food Supplements; Fortified Food; Frequencies; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Glioblastoma; Handedness; Health; Health Policy; Hereditary Retinoblastoma; Homozygote; Human; Hypermethylation; Incidence; Ingestion; Intake; Lead; Leukocytes; Lung; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methylation; Mexico; Modeling; Mothers; Mutation; Newly Diagnosed; Nonsense Codon; Nutrient; Persons; Plasma; Predisposition; Pregnancy; Pregnancy Trimesters; Promoter Regions; Prospective Studies; Prostate; Public Health; RB1 gene; Retina; Retinal; Retinoblastoma; Retinoblastoma Protein; Risk; Sampling; Site; Testing; Variant; Woman; Work; base; carcinogenesis; cohort; disease-causing mutation; early childhood; epigenome; folic acid metabolism; folic acid supplementation; high risk; in utero; lung small cell carcinoma; malignant breast neoplasm; mouse model; neurodevelopment; outcome forecast; prenatal; promoter; pyrosequencing; response; tumor; tumor DNA; tumor progression

 DESCRIPTION (provided by applicant): Synthetic folic acid supplements are consumed by 50% of US adults. High folic acid intake can result in CpG island hypermethylation. Recent studies suggest high intake may contribute to carcinogenesis particularly in those persons unable to metabolize folic acid efficiently such as persons homozygous for the 19bp deletion polymorphism in the dihydrofolate reductase(DHFR) gene (rs70991108). Homozygotes (19% of US adults) have less efficient conversion of synthetic folic acid into biological folate. Women homozygous for the DHFR19bp deletion (DHFR19bpdel) are at increased risk for having a child with retinoblastoma, a neuro-ectodermally derived early childhood cancer that has served as a model for understanding carcinogenesis. This risk appears elevated among women homozygous for DHFR19bpdel who consumed folic acid containing prenatal supplements in the first trimester. In retinoblastoma, 37% of disease-causing mutations in the CpG-rich gene, RB1, are due to deamination of methylated cytosines in RB1, while an additional 12% are caused by methylation of the RB1 promoter. We hypothesize that these methylation related RB1-inactivating changes may be induced by less functional genetic variations in folate metabolism and excess exposure in early retinal development. Murine models suggest particular sensitivity to folic acid exposure in early neural development. In humans, periods of dietary inadequacy in early gestation are associated with hyper-methylation at meta- stable epialleles. Pilot data from mutation assays and methylation arrays from our ongoing case-series study of newly diagnosed retinoblastoma (mean age 23 months) in Central Mexico, EpiRbMx, suggest that women who have the less efficient DHFR 19bpdel and high folic acid prenatally have higher risk of a child with a methylation related RB1-inactivating mutation or differentially hyper-methylated RB1 promoter directly resulting in tumor formation. Maternal DHFR19bpdel homozygosity combined with high prenatal folic acid intake may lead to RB1 hyper-methylation in developmentally susceptible cells, thereby contributing to carcinogenesis. Based on the results of our pilot data, we propose to use existing samples and data from 337 cases in our ongoing EpiRbMx study (founded in 2003) including pre-treatment measures of mother and child plasma nutrients, diet intake, genotype, and tumors, to test our hypothesis of an association between maternal DHFR 19bpdel and prenatal folic acid exposure (using plasma and intake measures) and 1) methylation related RB1 mutations, specifically in somatic (non-germline) RB1 mutations, and 2) methylation of the RB1 promoter. We will further examine the impact of DHFR and prenatal folic acid exposure on differential methylation in metastable epialleles to document their effect on the developing epigenome. Given the high frequency of RB1 mutations among poor prognosis adult tumors such as small cell lung cancer(54%) or glioblastoma(11%) and the high proportion (19%) of adults with less efficient folic acid metabolism, the potential translational impact of our study is high, as our results can inform public health policy and evaluation of synthetic folic acid exposure.

 描述（由适用提供）：合成叶酸补充剂被50％的美国成年人消费。高叶酸摄入会导致CpG岛高甲基化。最近的研究表明，高摄入量可能导致致癌作用，特别是在那些无法有效地代谢叶酸的人中，例如二氢叶酸酸酯还原酶（DHFR）基因（RS70991108）中19BP缺失多态性的人。纯合子（美国成年人中有19％）的合成叶酸效率较低，转化为生物叶酸。纯合为DHFR19BP缺失（DHFR19BPDEL）纯合的女性患有视网膜母细胞瘤的孩子的风险增加，这是一种神经性脱皮的儿童早期癌症，该癌症已成为理解癌变的模型。 DHFR19BPDEL纯合的女性中，这种风险似乎升高，她在头三个月消耗了含有产前补充剂的叶酸。在视网膜母细胞瘤中，富含CpG的基因RB1中有37％的引起疾病的突变是由于RB1中甲基化的胞嘧啶的脱氨酸，而另外12％是由RB1启动子的甲基化引起的。我们假设这些与甲基化相关的RB1灭活变化可能是由于叶酸代谢中功能较小的遗传变异而引起的，并且在早期剩余发育中超过了暴露。鼠模型表明，在早期神经发育中对叶酸暴露的敏感性特殊。在人类中，早期妊娠中饮食不足的时期与元明确的乳头上的高甲基化有关。来自我们正在进行的病例序列研究的突变测定和甲基化阵列的试验数据研究在墨西哥中部，新诊断的视网膜母细胞瘤（平均23个月）EpirBMX，表明患有效率较低的DHFR 19BPDEL且高叶酸的女性具有较高的与甲基化相关的rb1-Intriation-Intybriation-night Bys-Intription的较高的foRIC酸的风险，或者是甲基化较高的rB1-启动者的风险。形成。母体DHFR19BPDEL纯合性与高产前叶酸的摄入相结合可能导致发育易感细胞的RB1超甲基化，从而导致致癌。根据我们的试验数据的结果，我们建议在我们正在进行的EPIRBMX研究中使用337例病例的现有样品和数据（成立于2003年），包括对母亲和儿童血浆营养素，饮食摄入，基因型和肿瘤的预处理测量，以测试我们使用MATER DHFR 19bpdel和Pras Idic dientail Furnic forienic forianic folicatial forianic folicic foriency forcranic forcrance for and concrane dientail forianic forical diency forcrip forianic forical concion consecoper的测量。甲基化相关的RB1突变，特别是在体细胞（非网状）RB1突变中，以及2）RB1启动子的甲基化。我们将进一步研究DHFR和产前叶酸暴露对亚稳态甲基中差甲基化的影响，以记录其 对发展表观基因组的影响。鉴于不良预后的RB1突变频率很高，例如小细胞肺癌（54％）或胶质母细胞瘤（11％）和高效叶酸代谢效率较低的成年人的高比例（19％），我们研究的潜在翻译影响很高，因为我们的结果可能会导致公共卫生政策和评估合成酸性含量。