Gene-Environment Factors in Childhood Brain Tumors

描述(申请人提供)：儿童脑瘤(CBT)的环境和遗传原因在很大程度上是未知的，而且由于脑瘤相对罕见，包括来自多个地区的数据的合作是必要的。这项拨款重新提交是为了响应美国国家癌症研究所在脑肿瘤研究方面的几个优先研究重点，因为它寻求建立这样的合作，为未来的合作研究设定框架，并评估脑肿瘤的线索，在这种情况下，基因多态已知会影响杀虫剂和多环芳烃[PAH]的新陈代谢，这是儿童环境中常见的化学物质，可能与CBT有关。我们的初步研究(R03 CA106011，一项基于人群的功能性异种生物病例对照研究 代谢多态)确定了可能增加儿童对这些化学物质易感性的特定特征。在接触农药的儿童中，农药代谢基因(GSTT1、PON1)的多态与CBT风险增加2-3倍相关。EPHX1基因的多态与产前暴露于烟草烟雾中的儿童的风险增加5倍相关，EPHX1是代谢多环芳烃的重要因素。这些结果是基于只有66个病例和137个对照的DMA和访谈数据，它们需要用更大的研究来澄清。我们建议扩大我们的研究范围，以包括300名具有类似样本和暴露数据的额外受试者。继续关注功能多态性(主要在胎儿/儿童大脑中表达的基因)，我们建议确认我们的初步研究结果，与农药(PON1，GSTT1，CYP2E1)和多环芳烃(EPHX1，GSTP1，GSTM1)代谢有关，并考虑更多其产物代谢农药(BCHE，CYP2C19，CYP3A4，CYP2D6，CYP1A2，FMO1，FMO3，ALDH3A1，PON2)或PAH(MPO，SULT1A1，CYP1A1，CYP1B1，NQO1，GSTM3)的基因。了解这些可能有助于我们预防和治疗这种毁灭性的疾病。拟议的多州合作将探索影响个人如何处理体内常见环境暴露的基因的影响，特别是杀虫剂和多环芳烃、烟草烟雾、焦肉和汽车尾气中的化学物质。

DESCRIPTION (provided by applicant): The environmental and genetic causes of childhood brain tumors (CBT) are largely unknown, and because brain tumors are relatively rare, collaborations that include data from multiple regions are necessary. This grant resubmission is responsive to several National Cancer Institute research priorities for brain tumor studies, in that it seeks to establish such a collaboration, sets a framework for future cooperative studies, and evaluates leads on brain tumors, in this case, genetic polymorphisms that are known to affect the metabolism of pesticides and polycyclic aromatic hydrocarbons [PAH], chemicals common in children's environments and potentially related to CBT. Our pilot study (R03 CA106011, a population-based case-control study of functional xenobiotic metabolism polymorphisms) identified specific traits that may increase children's susceptibility to these chemicals. Polymorphisms in pesticide-metabolism genes (GSTT1, PON1) were associated with 2- to 3-fold increased risks of CBT among children with pesticide exposure. A polymorphism in EPHX1, important in metabolizing PAH, was associated with a 5-fold increased risk among children exposed prenatally to tobacco smoke. These results were based on DMA and interview data from only 66 cases and 137 controls, and they need to be clarified with a larger study. We propose to expand our study to include 300 additional subjects with similar specimens and exposure data. Continuing to focus on functional polymorphisms (mainly in genes expressed in fetal/childhood brain), we propose to confirm the findings of our pilot study related to pesticide (PON1, GSTT1, CYP2E1), and PAH (EPHX1, GSTP1, GSTM1) metabolism, and consider additional genes whose products metabolize pesticides (BCHE, CYP2C19, CYP3A4, CYP2D6, CYP1A2, FMO1, FMO3, ALDH3A1, PON2) or PAH (MPO, SULT1A1, CYP1A1, CYP1B1, NQO1, GSTM3).Lay Description: The causes of brain tumors in children are largely unknown, but both genes and environmental exposures are probably important. Understanding these may help us to prevent and treat this devastating disease. The proposed multi-state collaboration will explore the influence of genes that affect how individuals process common environmental exposures in the body, specifically pesticides and PAH, chemicals in tobacco smoke, charred meat and vehicle exhaust.