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

基本信息

批准号：
7240491
负责人：
RANDA A EL-ZEIN
金额：
$ 28.67万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7240491
关键词：
Age Archives Biological Markers Blood specimen Cell Cycle Cell Cycle Regulation Cessation of life Chromosomal Instability Chromosome abnormality Clinical Clinical Data Cytogenetic Analysis DNA DNA Repair DNA Repair Gene DNA Repair Pathway Data Death Certificates Death Records Development Disease Disease Outcome Disease Progression ERCC2 gene Early Diagnosis End Point Event Exhibits Family Cancer History Frequencies Gender Genes Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomic Instability Genotype Goals Health Hodgkin Disease Individual Malignant Neoplasms Measures Medical Records Modality Molecular Numbers Outcome Patients Play Population Predisposition Preventive Primary Neoplasm Proteins Recurrence Reporting Research Personnel Resources Risk Risk Factors Role Sampling Sister Chromatid Exchange Smoking Subgroup Survivors TP53 gene Telephone Interviews Testing Variant Vital Status XRCC1 gene XRCC3 gene Zein cohort follow-up information gathering insight mutant prognostic programs

Age Archives Biological Markers Blood specimen Cell Cycle Cell Cycle Regulation Cessation of life Chromosomal Instability Chromosome abnormality Clinical Clinical Data Cytogenetic Analysis DNA DNA Repair DNA Repair Gene DNA Repair Pathway Data Death Certificates Death Records Development Disease Disease Outcome Disease Progression ERCC2 gene Early Diagnosis End Point Event Exhibits Family Cancer History Frequencies Gender Genes Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomic Instability Genotype Goals Health Hodgkin Disease Individual Malignant Neoplasms Measures Medical Records Modality Molecular Numbers Outcome Patients Play Population Predisposition Preventive Primary Neoplasm Proteins Recurrence Reporting Research Personnel Resources Risk Risk Factors Role Sampling Sister Chromatid Exchange Smoking Subgroup Survivors TP53 gene Telephone Interviews Testing Variant Vital Status XRCC1 gene XRCC3 gene Zein cohort follow-up information gathering insight mutant prognostic programs

展开

项目摘要

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）：霍奇金氏病（HD）幸存者的主要关注点是复发或第二个原发性肿瘤的发展。尽管导致HD患者不利结局和差差的因素尚不完全了解，但风险最高的人群似乎在遗传上易于易受。在此提案中，我们建议在现有的254例HD患者中评估一组易感生物标志物作为疾病结果的预测指标，这些患者可为他们提供人口，流行病学，临床数据和预处理血液样本。我们将检验以下假设：与有利结果的患者相比，与具有良好结果的患者相比，与DNA修复能力差（通过增加染色体不稳定性的量度）和不良基因型（DNA修复和细胞周期控制中的多态性）患者更频繁地发生不利的结果。具体而言，我们建议：1）收集有关健康和重要状态数据的随访信息，以确定同类中所有HD患者的终点（复发或第二个原发性肿瘤）； 2）在表型上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）在SPT的复发或发育中的作用。我们假设结局较差的患者比有良好结果的患者表现出更高的基线染色体损伤水平。 3）阐明在DNA修复能力基因（XRCC1，XPD和XRCC3）中特异性多态性的作用以及细胞周期控制（p53基因）在HD结果调节中的作用。我们假设具有DNA修复等位基因变体的个体改变了DNA修复能力并增加了复发或SPT的风险。同样，p53基因的等位基因变体与变异蛋白有关，这种变异蛋白可能通过诱导基因组不稳定性和DNA失误而促进细胞周期控制的变异蛋白，或者通过允许突变体的存活，这又会对结果产生负面影响； 4）独立并共同分析流行病学和生物标志物数据，作为SPT的复发和发展的预测指标。鉴定出现增加或第二次原发性肿瘤发育风险增加的HD患者的亚组具有临床和预后相关性。高风险人群可以针对密集的预防和早期检测策略。