Biomarkers of survival in glioma epidemiology

描述（由申请人提供）：为了满足对成人胶质瘤改进治疗的巨大需求，本项目将评估肿瘤组织的分子特征、血清学免疫因子和遗传多态性作为患者生存的生物标志物。这些拟议的研究是对一项16年R 01资助的基于人群的病例对照研究和5年SPORE资助的UCSF神经肿瘤诊所（NOC）基于诊所的研究中正在招募的患者的补充。这些来源共同提供了该国最大的具有良好特征的成人胶质瘤患者数据集，包括多态性，血清学，肿瘤标志物，人口统计学和其他流行病学，治疗和生存数据。我们将继续确定1997-99年和2001-04年诊断的基于人群的成人发病胶质瘤病例的生命状态和相关治疗信息，以及通过UCSF NOC 2002-2006年（总数约1500）和（B）在UCSF NOC 2007-2011年中累积的约720例患者（问卷、血液、口腔和肿瘤标本）的患者。（另一项基于人群的系列研究将于2006年5月开始，这将使2006-2011年诊断的患者总数达到约960例）。在我们正在进行的研究和其他研究中发现的几种生物标志物值得进一步研究。在本提案的目标1，2中，我们将更深入地了解我们当前系列中观察到的血清IgE水平升高或处于正常或临界水平的胶质母细胞瘤病例中生存率提高的机制，并验证和扩展其他潜在相关血清标志物的发现图10显示了肿瘤标志物（sCD 23和sCD 14）、肿瘤标志物（CD 23蛋白和IL 13 RA 2 mRNA表达）和IL 4、IL 13、IL 4 R、IL 13 RA 1和IL 13 RA 2中的组成型SNP。还将评估这些标志物与肿瘤TP 53突变和表达以及EGFR扩增和表达的关系（在母研究R 01中测量的标志物）。在目标3中，我们将确定在存在或不存在肿瘤MGMT甲基化的情况下，MGMT或肿瘤TP 53突变或表达的多态性是否影响接受或未接受替莫唑胺治疗的患者的生存率。在目标4中，我们将在2007年7月1日至2011年6月30日在UCSF NOC的新诊断患者中验证从目标2和3中获得的有希望的标志物，其中约120例GM病例在临床试验方案中。识别与胶质瘤生存相关的预测性生物标志物可能有助于为每个胶质瘤患者选择最佳治疗方法，基于快速治疗评估的统一预后增强临床试验同质亚组的定义，并为患者提供更好的预后信息。公共卫生相关性：拟议的研究将有助于确定可能对治疗成人胶质瘤脑肿瘤有用的标志物。特异性治疗可能在某些显示特定遗传、免疫和肿瘤特征的患者群体中更有效。个体化脑肿瘤治疗与公共卫生和癌症医学的相关性在于使患者免受无效和潜在毒性治疗，同时将新的实验性治疗引导给那些可能从这些干预措施中获益最多的患者。

DESCRIPTION (provided by applicant): To address the great need for improved therapies for adult glioma, this project will evaluate molecular features of tumor tissue, serologic immune factors and genetic polymorphisms as biomarkers of patient surival. The proposed studies are additions to ongoing recruitment of patients in a 16 year R01 funded population-based case control study and 5 years of SPORE funded clinic-based research in the UCSF Neuro-oncology Clinic (NOC). Together these sources provide among the country s largest datasets of well-characterized adult glioma patients with polymorphism, serologic, tumor marker, demographic and other epidemiologic, treatment, and survival data. We will continue to determine vital status and relevant treatment information for population based adult onset glioma cases diagnosed 1997-99 and 2001-04 and patients accrued through the UCSF NOC 2002-2006 (total number ~1500) and (b) accrue ~720 patients (questionnaire, blood, buccal, and tumor specimens) in the UCSF NOC 2007-2011. (Another population based series to begin May 2006 will bring the total number of patients diagnosed from 2006-2011 to ~960). Several biomarkers identified in our ongoing and other studies warrant further research. In Aims 1,2 of this proposal we will obtain a greater understanding of the mechanisms of improved survival among glioblastoma cases with elevated versus normal or borderline serum IgE levels observed in our current series and validate and expand findings to other potentially related serum markers (sCD23 and sCD14), tumor markers (CD23 protein and IL13RA2 mRNA expression), and constitutive SNPs in IL4, IL13, IL4R, IL13RA1, and IL13RA2. These markers will also be assessed in relation to tumor TP53 mutation and expression and EGFR amplification and expression (markers measured in the parent R01 study). In Aim 3 we will determine whether polymorphisms in MGMT or tumor TP53 mutation or expression influence survival in the presence or absence of tumor MGMT methylation in patients treated or not treated with temozolomide. In Aim 4 we will validate promising markers obtained from Aims 2 and 3 in newly diagnosed patients seen at the UCSF NOC from July 1, 2007-June 30, 2011 in ~120 of these GM cases on clinical trial protocols. Identification of predictive biomarkers related glioma survival is likely to aid in choosing the best treatments for each glioma patient, in enhancing definition of homogeneous subgroups for clinical trials based on uniform prognosis for rapid treatment evaluation, and in providing better prognostic information to patients. PUBLIC HEALTH RELEVANCE: The proposed study will help identify markers that may be useful in the treatment of adult glioma brain tumors. Specific therapies may be more effective in some patient groups that display specific genetic, immulogical, and tumor characteristics. The relevance of individualizing brain tumor treatment to public health and cancer medicine lies in sparing patients ineffective and potentially toxic therapies while guideing newer experimental treatments to those patients who may benefit the most from such interventions.