Genetic and Molecular Epidemiology of Adult Glioma

恶性神经胶质瘤使人衰弱并迅速致命。越来越明显的是，在主要的组织学类型的胶质瘤中存在着大量的病因异质性。这可能部分解释了为什么没有优势的病因危险因素已经出现了以前牵连的各种因素。 我们研究的目的是确定遗传定义的胶质瘤亚组的重要危险因素。 这种竞争性更新是从我们和其他人的结果中发展而来的，这些结果表明，标准的胶质瘤风险因素，如年龄，种族和性别，以及某些感染和过敏史，血清学因素，饮食致癌物和抗氧化剂，以及解毒和DNA修复的遗传变异可能会对特定组织学和遗传学定义的胶质瘤亚组的风险产生差异性影响。 我们将建立在我们的两个人口为基础的系列，以进一步了解遗传调制的环境和宿主因素影响胶质瘤的发生。 我们将使用快速病例确定和Kaiser Permanente诊所以及通过随机数字拨号获得的适当人群对照，在旧金山弗朗西斯科地区的六个县，从2001年1月11日至2004年1月12日诊断出另外700例神经胶质瘤病例。与我们现有的问卷进行面对面访谈，可以获得许多相关因素的信息，包括家庭和个人病史、职业和饮食偏好。将从所有自愿的受试者中采集血液和口腔标本，并从病例中采集病理学报告、切片和肿瘤组织。 对于在Kaiser Permanente诊断的病例，将在手术前采集血液标本。 我们将（1）根据p53、EGFR和MDM 2的表达以及p53突变、EGFR和MDM 2扩增和p14 arf和p16缺失对星形细胞肿瘤进行分类;（2）解毒、DNA修复和免疫功能相关基因的基因型（谷胱甘肽转移酶μ和θ、环氧化物水解酶、ERCC 1、ERCC 2、XRCC 1和烷基鸟嘌呤转移酶、IL-4 R、IL-13、IL-13 R和RANTES）;（3）测定受试者对水痘带状疱疹、其他疱疹病毒和某些过敏原的抗体，并确定T细胞对这些抗原攻击的增殖;（4）基于初步数据测试几个特定的假设;（5）比较组织学或分子学定义的病例亚组与对照的基因型、血清学、过敏，饮食和其他危险因素与多重逻辑回归;和（6）确定短期胶质瘤存活是否与研究因素相关，以改进关于胶质瘤发生与肿瘤进展中因素的影响的推断。

Malignant gliomas are debilitating and rapidly fatal. It is increasingly evident that substantial etiologic heterogeneity exists within major histologic types of glioma. This may partly explain why no dominant etiologic risk factors have emerged from the diverse factors previously implicated. The purpose of our research is to identify important risk factors for genetically defined subgroups of glioma. This competitive renewal evolved from our and others' results suggesting that standard glioma risk factors such as age, ethnicity, and gender, as well as history of certain infections and allergies, serologic factors, dietary carcinogens and antioxidants, and genetic variation in detoxification and DNA repair may differentially influence risk to specific histologic and genetically defined subgroups of glioma. We will build on our two population based series to further the understanding of genetic modulation of environmental and host factors influencing gliomagenesis. We will accrue another 700 glioma cases diagnosed from 11/1/01- 12/1/04 in six San Francisco area counties using rapid case ascertainment and Kaiser Permanente clinics and appropriate population based controls obtained through random-digit dialing. In-person interviews with our existing questionnaires elicit information on many relevant factors including family and personal medical histories, occupation, and dietary preferences. Blood and buccal specimens will be collected from all willing subjects and pathology reports, slides and tumor tissue will be collected from cases. Blood specimens will be collected prior to surgery for cases diagnosed at Kaiser Permanente. We will (1) categorize astrocytic tumors according to expression of p53, EGFR, and MDM2 and to p53 mutation, EGFR and MDM2 amplifications and p14arf and p16 deletions; (2) genotype subjects for pertinent detoxification, DNA repair and immune function genes (glutathione transferase mu and theta, epoxide hydrolase, ERCC1, ERCC2, XRCC1, and alkylguanine transferase, IL-4R, IL-13, IL-13R and RANTES); (3) assay subjects' antibodies to varicella zoster, other herpes viruses and certain allergens and determine T-cell proliferation to these antigenic challenges; (4) test several specific hypotheses based on preliminary data; (5) compare histologically or molecularly defined case subgroups with controls for genotypes, serologies, allergies, dietary and other risk factors with multiple logistic regressions; and (6) determine if short- term glioma survival is associated with study factors to refine inferences about effects of factors in gliomagenesis versus tumor progression.