Molecular Biomarkers as Predictors of Hodgkin's Disease

分子生物标志物作为霍奇金病的预测因子

• 批准号: 6680963
• 负责人: RANDA A EL-ZEIN
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680963
• 关键词: DNA repair; Hodgkin's disease; biomarker; cell cycle; chromosome aberrations; clinical research; cytogenetics; fluorescent in situ hybridization; genetic crossing over; genetic polymorphism; genetic susceptibility; human genetic material tag; human subject; human tissue; interview; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; outcomes research; p53 gene /protein; patient oriented research; prognosis

DESCRIPTION (provided by applicant): A major concern for Hodgkin's Disease (HD) survivors is the development of recurrence or second primary tumors. Although factors responsible for the unfavorable outcomes and poor survival of HD patients remain incompletely understood, the population at highest risk seems to be genetically predisposed. In this proposal we propose to evaluate a panel of susceptibility biomarkers as predictors of disease outcome in an existing cohort of 254 HD patients for whom demographic, epidemiological, clinical data and pretreatment blood samples are available. We will test the hypothesis that unfavorable outcomes occur more frequently in patients with poor DNA repair capacity (measures by increase chromosome instability) and with adverse genotypes (polymorphisms in DNA repair and cell cycle control) as compared with patients with favorable outcome. Specifically we propose: 1) To collect follow-up information on health and vital status data to ascertain endpoints (recurrence or second primary tumors) for all the HD patients in the cohort; 2) To phenotypically characterize the role of background chromosomal instability (measured by chromosome aberrations and sister chromatid exchanges) in disease recurrence or development of SPTs. We hypothesize that patients with poor outcomes exhibit higher levels of baseline chromosomal damage than patients with favorable outcome. 3) To elucidate the role that specific polymorphisms in DNA repair capacity genes (XRCC1, XPD and XRCC3) and cell cycle control (p53 gene) play in the modulation of HD outcome. We hypothesize that individuals with DNA repair allelic variants have altered DNA repair capacity and increased risk of developing recurrence or SPT. Similarly, the allelic variants of p53 gene are associated with variant proteins that may alter cell cycle control encouraging progression either by inducing genomic instability and DNA misrepair or by permitting survival of mutants which will in turn have a negative impact on outcome; and 4) To analyze epidemiological and biomarker data independently and jointly as predictors of recurrence and development of SPTs. Identification of subgroups of HD patients who are at increased risk for recurrence or second primary tumor development has both clinical and prognostic relevance. The high risk population can be targeted for intensive preventive and early detection strategies.

描述（由申请人提供）：霍奇金病（HD）幸存者的主要关注点是复发或第二原发肿瘤的发展。尽管导致HD患者不良预后和低生存率的因素仍不完全清楚，但高危人群似乎有遗传倾向。在这项提案中，我们建议评估一组易感性生物标志物作为疾病结局的预测因子，在现有的254名HD患者队列中，这些患者有人口统计学、流行病学、临床数据和预处理血液样本。与结果良好的患者相比，DNA修复能力差（通过增加染色体不稳定性来衡量）和不良基因型（DNA修复和细胞周期控制的多态性）的患者更容易出现不良结果，我们将验证这一假设。具体而言，我们建议：1)收集所有HD患者的健康和生命状态数据的随访信息，以确定终点（复发或第二原发肿瘤）；2)表型表征背景染色体不稳定性（通过染色体畸变和姐妹染色单体交换测量）在SPTs疾病复发或发展中的作用。我们假设预后较差的患者比预后良好的患者表现出更高水平的基线染色体损伤。3)阐明DNA修复能力基因（XRCC1、XPD和XRCC3）和细胞周期控制基因（p53基因）特异性多态性在HD预后调节中的作用。我们假设具有DNA修复等位基因变异的个体改变了DNA修复能力并增加了复发或SPT的风险。同样，p53基因的等位基因变异与可能改变细胞周期控制的变异蛋白相关，通过诱导基因组不稳定和DNA错误修复或通过允许突变体存活而反过来对结果产生负面影响，从而促进进展；4)独立或联合分析流行病学和生物标志物数据作为SPTs复发和发展的预测因素。确定复发或第二原发肿瘤风险增加的HD患者亚组具有临床和预后相关性。可以针对高危人群实施强化预防和早期发现战略。