Genetic and Molecular Epidemiology of Adult Glioma

成人胶质瘤的遗传和分子流行病学

• 批准号: 6326317
• 负责人: MARGARET R. WRENSCH
• 金额: $ 108.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6326317
• 关键词: DNA repair; allergens; antiviral antibody; astrocytes; cancer risk; clinical research; disease /disorder etiology; enzyme activity; epidermal growth factor; epoxide hydrolase; genetic polymorphism; glioma; glutathione transferase; growth factor receptors; human subject; immunocytochemistry; interleukin 13; interleukin 4; methylguanine DNA methyltransferase; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer immunology; p53 gene /protein; varicella zoster virus

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.

恶性神经胶质瘤使人衰弱并迅速致命。越来越明显的是，胶质瘤的主要组织学类型之间存在着实质性的病因异质性。这可能部分解释了为什么从先前涉及的多种因素中没有出现主要的病因危险因素。我们研究的目的是确定神经胶质瘤遗传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，标准的胶质瘤危险因素，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、解毒和DNA修复的遗传变异，可能会对特定组织学和遗传定义的胶质瘤亚群的风险产生不同的影响。我们将建立在我们的两个基于人群的系列，以进一步了解影响胶质瘤形成的环境和宿主因素的遗传调节。我们将收集另外700例胶质瘤病例，从2001年11月1日至2004年12月1日在旧金山地区的6个县，使用快速病例确定和Kaiser Permanente诊所，并通过随机数字拨号获得适当的基于人群的对照。通过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。将收集所有自愿受试者的血液和口腔标本，并收集病例的病理报告、载玻片和肿瘤组织。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MDM2的表达以及p53突变、EGFR和MDM2扩增和p14arf和p16缺失对星形细胞肿瘤进行分类；(2)对相关解毒、DNA修复和免疫功能基因（谷胱甘肽转移酶mu和theta、环氧化物水解酶、ERCC1、ERCC2、XRCC1、烷基鸟嘌呤转移酶、IL-4R、IL-13、IL-13R和RANTES）进行基因分型；(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，并测定t细胞对这些抗原挑战的增殖；(4)根据初步数据检验若干具体假设；(5)将组织学或分子定义的病例亚组与对照进行基因型、血清学、过敏、饮食和其他危险因素的多重logistic回归比较；(6)确定胶质瘤的短期生存是否与研究因素相关，以完善胶质瘤发生与肿瘤进展中因素影响的推断。