Gene-Environment Factors in Childhood Brain Tumors

描述（由申请人提供）：儿童脑肿瘤（CBT）的环境和遗传原因在很大程度上是未知的，并且由于脑肿瘤相对罕见，包括来自多个地区的数据的合作是必要的。此次拨款重新提交是对国家癌症研究所脑肿瘤研究的几个优先事项的回应，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，已知的影响农药和多环芳烃代谢的遗传多态性[PAH]，儿童环境中常见的化学物质，可能与CBT有关。我们的试点研究（R03 CA106011）是一项基于人群的功能性外源性药物病例对照研究

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.