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

摘要 项目3 -产前暴露、组成遗传学、DNA甲基化和儿童白血病 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可以治疗， 导致长期发病。预防白血病需要了解其原因。上一 我们发现，儿童白血病肿瘤细胞从前B细胞前体发生了深刻的改变， 关于DNA甲基化;即，在白血病发生过程中，完全10%的CpG位点的甲基化发生改变。 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（加州）中发现其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 局部和全基因组。虽然研究人员越来越关注环境和遗传 DNA甲基化变异的原因，很少有人能解释两者结合的影响。 因素我们将在本提案中解决这一知识差距。首先，我们将使用全基因组DNA单克隆 核苷酸多态性（SNP）数据，以评估遗传变异对200例 急性淋巴细胞白血病（ALL）病例和400例对照，来自加州母婴出生队列。一 第二组200例ALL病例和400例对照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/对照组来研究遗传和 环境因素对DNA甲基化和ALL风险的影响项目2中确定的ALL化学风险因素 在下一个资助周期，我们的研究先前确定的ALL的化学风险因素 在项目1中确定的ALL免疫风险因素将用于拟定的项目3统计 分析.项目3中使用的400例病例和800例对照（两组）的生物标本将 与项目1中评估的细胞因子和评估的蛋白加合物完全重叠， 2号工程中的小分子。最后，我们将使用一个小鼠模型，概括了人类的特征， 儿童白血病，以直接评估子宫内特定化学品暴露对DNA甲基化的影响 在前B细胞（我们的靶细胞群）中，以及在白血病发生中。

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.