Biomarkers of survival in glioma epidemiology

描述（由申请人提供）：为了满足成人神经胶质瘤改进治疗的巨大需求，该项目将评估肿瘤组织的分子特征、血清免疫因子和遗传多态性作为患者生存的生物标志物。拟议的研究是对 UCSF 神经肿瘤诊所 (NOC) 正在进行的 16 年 R01 资助的基于人群的病例对照研究和 5 年 SPORE 资助的基于临床的研究的患者招募的补充。这些来源共同提供了全国最大的成人神经胶质瘤患者数据集，其中包括多态性、血清学、肿瘤标志物、人口统计和其他流行病学、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以及 2002-2006 年通过 UCSF NOC 累积的患者（总数约 1500 例）的生命状态和相关治疗信息，以及 (b) 在 UCSF NOC 中累积约 720 名患者（问卷、血液、口腔和肿瘤标本） 2007-2011。 （另一个基于人口的系列研究将于 2006 年 5 月开始，将使 2006 年至 2011 年诊断的患者总数达到约 960 例）。我们正在进行的研究和其他研究中发现的一些生物标志物值得进一步研究。在本提案的目标 1,2 中，我们将更好地了解在我们当前系列中观察到的血清 IgE 水平高于正常或临界水平的胶质母细胞瘤病例中改善生存的机制，并验证和扩展其他潜在相关血清标志物（sCD23 和 sCD14）、肿瘤标志物（CD23 蛋白和 IL13RA2 mRNA 表达）以及 IL4、IL13、IL4R、IL13RA1 和IL13RA2。这些标记物还将根据肿瘤 TP53 突变和表达以及 EGFR 扩增和表达（在母 R01 研究中测量的标记物）进行评估。在目标 3 中，我们将确定在接受或未接受替莫唑胺治疗的患者中，在存在或不存在肿瘤 MGMT 甲基化的情况下，MGMT 多态性或肿瘤 TP53 突变或表达是否影响生存。在目标 4 中，我们将在 2007 年 7 月 1 日至 2011 年 6 月 30 日期间在 UCSF NOC 就诊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，其中大约有 120 例根据临床试验方案的 GM 病例。识别与神经胶质瘤生存相关的预测生物标志物可能有助于为每位神经胶质瘤患者选择最佳治疗方法，增强基于统一预后的临床试验同质亚组的定义，以进行快速治疗评估，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识别可能对治疗成人神经胶质瘤脑肿瘤有用的标记物。对于某些表现出特定遗传、免疫学和肿瘤特征的患者群体，特定疗法可能更有效。个体化脑肿瘤治疗与公共卫生和癌症医学的相关性在于避免患者接受无效和潜在毒性的治疗，同时为那些可能从此类干预措施中受益最大的患者提供新的实验性治疗。

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.