Exploring Gene-Environment Factors in Child Brain Tumors

描述(由申请人提供)： 儿童脑瘤(CBT)的病因在很大程度上是未知的。环境暴露被认为是由于胎儿和幼儿大脑对环境毒素的脆弱性而起到的作用。该项目将改善我们对环境和遗传因素在CBT发生中的有限关系的了解，提供关于CBT病例和对照中选定的多态频率的必要的初步数据，并证明从基于人群的CBT流行病学研究中测量新生儿干血斑(DBS)中的多态的可行性，从而为更大规模的CBT研究检测基因和环境奠定基础。我们有机会有效和经济地获得这一信息，因为已经获得了标本和接触数据。我们建议测量从66例CBT病例和237名对照收集的DBS中编码酶的基因的多态性，这些酶代谢可能与CBT发生相关的化学物质。我们将比较下列基因的多态：1)细胞色素P-450(CYP)2E1和CYP 2D6，编码将亚硝胺和其他化学品激活为致癌中间体的I相酶；2)谷胱甘肽S转移酶(GST)(GSTP1、GSTT1和GSTM1)，编码解毒有机氯农药、亚硝脲、CYP激活的亚硝胺、多环芳烃(PAH)的第二相酶；3)微体环氧化物水解酶，与将多环芳烃激活为致癌中间体有关；4)对氧磷酶(PON1)，在常见的有机磷农药(毒死磷)的代谢物解毒中可能非常重要。尽可能利用这些数据，我们将描述组织学类别内的多态和诊断时年龄的多态，并检查它们与相关环境暴露的关系，在具有产前和儿童早期暴露数据的受试者子集中。

DESCRIPTION (provided by applicant): The causes of childhood brain tumors (CBT) are largely unknown. Environmental exposures are thought to play a role due to the vulnerability of fetal and early childhood brain to environmental toxins. This project would improve our limited understanding of the relationships of environmental and genetic factors in CBT occurrence by providing necessary preliminary data about the frequency of selected polymorphisms in CBT cases and controls, and demonstrating the feasibility of measuring polymorphisms in dried blood spots (DBS) from newborn screening archives for population-based epidemiologic studies of CBT, thus positioning us for larger CBT studies examining genes and environment. We have an opportunity to gain this information efficiently and economically, as specimens and exposure data already have been obtained. We propose to measure polymorphisms for genes which code for enzymes that metabolize chemicals potentially related to CBT occurrence, in DBS collected from 66 CBT cases and 237 controls. We will compare polymorphisms for the following genes: 1) Cytochrome P-450 (CYP) 2E1 and CYP 2D6, coding Phase I enzymes that activate nitrosamines and other chemicals into cancer-causing intermediates; 2) Glutathione S-transferase (GST) (GSTP1, GSTT1, and GSTM1), which code for Phase II enzymes that detoxify organochlorine pesticides, nitrosoureas, CYP-activated nitrosamines, polycyclic aromatic hydrocarbons (PAH); 3) Microsomal epoxide hydrolase, relevant to activation of PAHs into cancer-causing intermediates; 4) Paraoxonase (PON1), potentially important in detoxifying metabolites of the common organophosphate (OP) insecticides chlorpyrifos and diazinon. To the extent possible with these data, we will describe polymorphisms within histologic categories and by age at diagnosis, and examine their relationship with relevant environmental exposures among a subset of subjects with exposure data for the prenatal and early childhood periods.