Project 3 - Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia

摘要 项目3--产前暴露、构成遗传学、DNA甲基化与儿童白血病 前B细胞白血病是儿童中最常见的癌症，尽管在大多数情况下是可以治疗的，但这种疾病 会导致长期的发病率。预防白血病需要了解其原因。在上一次 资助周期，我们发现儿童白血病肿瘤细胞与前B细胞前体细胞发生了深刻的变化 至于DNA甲基化，即足足10%的CpG位点的甲基化在白血病发生过程中发生了变化。 环境风险因素，包括化学因素(多环芳烃)和饮食因素 (叶酸)，在我们的流行病学研究(加利福尼亚州)中发现它们会影响儿童白血病风险 儿童白血病研究(CCLS)，也影响DNA甲基化。遗传风险因素影响DNA甲基化 局部的和全基因组的。虽然研究人员越来越关注环境和遗传因素 DNA甲基化变异的原因，很少有人解释两者结合的影响 各种因素。我们将在目前的提案中解决这一知识差距。首先，我们将使用全基因组DNA单个 评估200名人群中遗传变异对DNA甲基化影响的核苷酸多态(SNP)数据 来自加州母婴出生队列的急性淋巴细胞白血病(ALL)病例和400名对照。一个 第二组200例急性淋巴细胞白血病患者和400例对照的CCLS受试者将用于重复和荟萃分析。 作为第二个目标，我们将使用相同的两个病例/对照集合来研究遗传和 环境因素对DNA甲基化和所有风险的影响。项目2中确定的所有人的化学风险因素 在下一个资助周期中，我们的研究确定了所有这些因素的化学风险因素 项目1中确定的所有免疫风险因素将在拟议的项目3统计中使用 分析。项目3中使用的400个病例和800个对照(两组)的生物样本将 与项目1中评估的细胞因子和蛋白质加合物评估的结果完全重叠 项目2中的小分子。最后，我们将使用一个概括人类特征的小鼠模型 儿童白血病直接评估子宫内化学暴露对DNA甲基化的影响 前B细胞(我们的目标细胞群)，以及白血病的发生。

ABSTRACT Project 3 – Prenatal Exposures, Constitutive Genetics, DNA Methylation & Childhood Leukemia Pre-B cell leukemia is the most common cancer in children, and though treatable in most cases, the disease leads to long-term morbidity. Preventing leukemia requires an understanding of its causes. In the previous funding cycle, we found that childhood leukemia tumor cells are profoundly altered from pre-B cell precursors with regards to DNA methylation; i.e., methylation of fully 10% of CpG sites is altered during leukemogenesis. Environmental risk factors, including chemical factors (polycyclic aromatic hydrocarbons) and dietary factors (folic acid), which were found to impact childhood leukemia risk in our epidemiology study (California Childhood Leukemia Study, CCLS), also affect DNA methylation. Genetic risk factors impact DNA methylation locally and genome-wide. While researchers have increasingly focused on the environmental and genetic causes of variation in DNA methylation, few have accounted for the impact of the combination of the two factors. We will address this knowledge gap in the current proposal. First, we will use genome-wide DNA single nucleotide polymorphism (SNP) data to assess the impact of genetic variation on DNA methylation among 200 acute lymphoblastic leukemia (ALL) cases and 400 controls from the California Mother-Child Birth Cohort. A second set of 200 ALL cases and 400 controls of CCLS subjects will be used for replication and meta-analysis. As a second aim, we will use the same two case/control sets to investigate the effects of both genetic and environmental factors on DNA methylation and ALL risk. Chemical risk factors for ALL identified in Project 2 during the next funding cycle, chemical risk factors for ALL that were previously identified by our research group, and immune risk factors for ALL identified in Project 1 will be used in the proposed Project 3 statistical analysis. The biospecimens from 400 cases and 800 controls (two sets together) used in Project 3 will completely overlap with those assessed for cytokines in Project 1 and those assessed for protein adducts and small molecules in Project 2. Finally, we will use a mouse model that recapitulates the features of human childhood leukemia to directly assess the effects of particular in utero chemical exposures on DNA methylation in pre-B cells (our target cell population), as well as on leukemogenesis.