Genetic and Epigenetic Biomarkers for B-cell Lymphoma

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL）是美国最常见的非霍奇金淋巴瘤。 States.所有DLBCL中有一半不能用标准的利妥昔单抗免疫化疗方案治愈， 环磷酰胺、阿霉素、长春新碱和泼尼松（R-CHOP）。目前，最常用的工具 决定DLBLC预后的是国际预后指数（IPI），该指数基于五项临床指标， 特征（患者年龄，肿瘤分期，血清乳酸脱氢酶浓度，体力状态， 和结节病部位的数量）。然而，具有相同IPI评分的DLBCL患者表现出明显的变异性 在生存率方面，表明在每个IPI类别中存在显著的残余异质性。的tp 53 基因编码p53肿瘤抑制因子，人类基因组的守护者。p53不能正常工作 在大多数人类肿瘤中，TP 53基因突变的直接结果是失活，但只有约50%的人失活。 人类肿瘤。p53通路的失调在淋巴结转移的发病机制中很重要。 恶性肿瘤，包括DLBCL，尽管TP 53编码序列突变发生在约20%的DLBCL中 患者通过我们与国际DLBCL R-CHOP联盟的合作，该联盟由25个医疗机构组成， 中心，我们获得的信息导致我们提出的假设，在这里测试：遗传和非遗传 来自TP 53基因的生物标志物单独或与其它异常组合可以预测临床行为。 在本申请中，我们提出了三个目标来研究这些可疑生物标志物的潜力。在目标#1中，我们 将确定IPI和免疫组织化学生物标志物（包括p53）的组合是否是一种免疫反应。 在预测DLBCL预后方面，IPI模型比单独使用IPI模型在临床上更准确。在目标#2中，我们将确定 TP 53 3 3'非翻译区中的单核苷酸变体和 TP 53编码序列是DLBCL预后的生物标志物。在目标#3中，我们将确定是否循环 miRNA和游离DNA是DLBCL预后和复发检测的生物标志物。实现目标 该提案将揭开DLBCL中新型非编码生物标志物的面纱，从而开启一个新的、未探索的领域 研究领域的预后，治疗决策，并可能药物开发的广泛范围 癌症。

Project Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma in the United States. Half of all DLBCLs cannot be cured with the standard immuno-chemotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Currently, the most common tool for determining DLBLC prognosis is the International Prognostic Index (IPI), which is based on five clinical characteristics (patient age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites). Yet DLBCL patients with identical IPI scores exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The TP53 gene encodes the p53 tumor suppressor, the guardian of the human genome. p53 does not function properly in most human tumors, yet it is inactivated as a direct result of mutations of the TP53 gene in only about 50% of human tumors. Dysregulation of the p53 pathway is important to the pathogenesis of lymphoid malignancies, including DLBCL, though mutations in the TP53 coding sequence occur in about 20% of DLBCL patients. Through our work with the International DLBCL R-CHOP Consortium, which consists of 25 medical centers, we obtained information leading to the hypothesis we propose to test here: genetic and non-genetic biomarkers from the TP53 gene alone or in combination with other abnormalities can predict clinical behavior. In this application, we propose three aims to study the potential of these suspected biomarkers. In Aim #1, we will determine whether the combination of the IPI and immunohistochemical biomarkers, including p53, is a more clinically accurate model than the IPI alone for predicting DLBCL prognosis. In Aim #2, we will determine whether the combination of single-nucleotide variants in the TP53 3' untranslated region and mutations in the TP53 coding sequence is a biomarker for DLBCL prognosis. In Aim #3, we will determine whether circulating miRNAs and cell-free DNA are biomarkers for prognosis and relapse detection for DLBCL. Achieving the aims in this proposal will unravel novel noncoding biomarkers in DLBCL and thereby open a new and unexplored area of investigation for prognosis, treatment decision making, and possibly drug development for a wide range of cancers.