Genetic and Molecular Epidemiology of Adult Glioma

恶性胶质瘤使人虚弱，而且很快就会致命。越来越明显的是，在主要组织学类型的胶质瘤中存在实质性的病因学异质性。这可能在一定程度上解释了为什么以前涉及的各种因素中没有出现明显的病因风险因素。我们研究的目的是确定基因定义的胶质瘤亚群的重要危险因素。这种竞争性更新是从我们和其他人的结果演变而来的，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、饮食致癌物质和抗氧化剂，以及在解毒和DNA修复方面的遗传变异，可能会对特定组织学和基因定义的胶质瘤亚群的风险产生不同的影响。我们将在我们的两个基于种群的系列的基础上，进一步了解影响胶质瘤发生的环境和宿主因素的遗传调控。我们将利用快速病例确定和Kaiser Permanente诊所以及通过随机数字拨号获得的适当的基于人群的对照，在旧金山地区的六个县于11/1/01-12/1/04年11/1-12/1期间再增加700例确诊的胶质瘤病例。通过与我们现有的问卷进行面对面的访谈，我们获得了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。将从所有有意愿的受试者身上采集血液和口腔样本，并从病例中收集病理报告、切片和肿瘤组织。对于在Kaiser Permanente确诊的病例，将在手术前收集血液样本。我们将(1)根据P53、EGFR和MDM2的表达以及P53突变、EGFR和MDM2扩增以及p14ARF和p16缺失来对星形细胞肿瘤进行分类；(2)根据相关解毒、DNA修复和免疫功能基因(谷胱甘肽转移酶、环氧化物水解酶、ERCC1、ERCC2、XRCC1和烷基鸟嘌呤转移酶、IL-4R、IL-13、IL-13R和RANTES)对受试者进行分型；(3)检测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，并确定针对这些抗原挑战的T细胞增殖；(4)基于初步数据测试几种特异性假说；(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、饮食和其他具有多因素Logistic回归的危险因素；以及(6)确定短期胶质瘤存活率是否与研究因素有关，以完善关于因素在胶质瘤形成与肿瘤进展中的作用的推断。

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.