Molecular Biomarkers as Predictors of Hodgkin's Disease

描述（由申请人提供）：霍奇金病（HD）幸存者的主要担忧是复发或第二原发肿瘤的发展。尽管导致HD患者不良结果和生存率低的因素尚不完全清楚，但风险最高的人群似乎具有遗传倾向。在本提案中，我们建议评估一组易感性生物标志物，作为现有 254 名 HD 患者队列中疾病结果的预测因子，这些患者的人口统计学、流行病学、临床数据和治疗前血液样本均可用。我们将检验以下假设：与具有良好结果的患者相比，具有较差 DNA 修复能力（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中的多态性）的患者更容易出现不良结果。具体来说，我们建议：1）收集有关健康和生命状态数据的随访信息，以确定队列中所有 HD 患者的终点（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）在疾病复发或 SPT 发展中的作用。我们假设预后不良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（p53基因）的特定多态性在HD结果调节中的作用。我们假设具有 DNA 修复等位基因变异的个体已经改变了 DNA 修复能力并增加了发生复发或 SPT 的风险。同样，p53 基因的等位基因变异与变异蛋白相关，这些变异蛋白可能会改变细胞周期控制，通过诱导基因组不稳定和 DNA 错误修复或允许突变体生存，从而促进进展，从而对结果产生负面影响； 4) 独立和联合分析流行病学和生物标志物数据，作为 SPT 复发和发展的预测因子。识别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。可以针对高风险人群采取强化预防和早期检测策略。

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.