Genetic and Epigenetic Biomarkers for B-cell Lymphoma

B 细胞淋巴瘤的遗传和表观遗传生物标志物

• 批准号: 10048471
• 负责人: KEN H YOUNG
• 金额: $ 20.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10048471
• 关键词: 3' Untranslated Regions; Aftercare; Age; Area; B-Cell Lymphomas; Behavior; Biological Markers; Cancer Biology; Cancer Prognosis; Categories; Cells; Characteristics; Clinical; Clinical Trials; Code; Combined Modality Therapy; Cyclophosphamide; DNA Sequence Alteration; Decision Making; Detection; Development; Disease; Disease Progression; Doxorubicin; Exhibits; Extranodal; Gene Mutation; Genetic; Genetic Markers; Goals; Hematologic Neoplasms; Heterogeneity; Human; Human Genome; Immunohistochemistry; International; International Prognostic Index; Investigation; Lactate Dehydrogenase; Lymphoma; MYC gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Medical center; MicroRNAs; Modeling; Molecular; Mutation; Non-Hodgkin' s Lymphoma; Nucleotides; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Performance Status; Pharmacotherapy; Plasma; Plasma Cells; Prednisone; Progression-Free Survivals; Public Health; Recurrence; Recurrent disease; Refractory Disease; Regimen; Relapse; Residual state; Risk; Sampling; Serum; Site; Survival Rate; TP53 gene; TP53 gene; Testing; Therapy Clinical Trials; Tumor Suppressor Proteins; Tumor stage; United States; Untranslated RNA; Untranslated Regions; Variant; Vincristine; Work; base; cancer risk; cell free DNA; circulating microRNA; clinical application; clinical practice; clinical predictors; drug development; epigenetic marker; gene translocation; immunohistochemical markers; improved; large cell Diffuse non-Hodgkin' s lymphoma; mutant; non-genetic; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; patient stratification; predictive modeling; prognostic; prognostic significance; relapse prediction; rituximab; tool; treatment response; treatment stratification; tumor; virtual

Genetic and Epigenetic Biomarkers for B-cell Lymphoma 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.

B细胞淋巴瘤的遗传和表观遗传生物标志物 摘要 弥漫性大B细胞淋巴瘤是美国最常见的非霍奇金淋巴瘤 各州。一半的DLBCL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、长春新碱和强的松(R-CHOP)。目前，最常见的工具是 决定DLBLC预后的是国际预后指数(IPI)，该指数基于五个临床指标 特征(患者年龄、肿瘤分期、血清乳酸脱氢酶浓度、运动状态、 和结外病变部位的数量)。然而，IPI评分相同的DLBCL患者表现出明显的变异性 在存活率方面，这表明在每个IPI类别中存在显著的残余异质性。TP53 该基因编码P53肿瘤抑制基因，是人类基因组的守护神。P53不能正常工作 在大多数人类肿瘤中，它被灭活的直接原因是TP53基因的突变，仅有50%左右。 人类肿瘤。P53通路异常在淋巴组织的发病机制中起重要作用 恶性肿瘤，包括DLBCL，尽管TP53编码序列突变发生在大约20%的DLBCL中 病人。通过我们与国际DLBCL R-CHOP联盟的合作，该联盟由25名医生组成 中心，我们获得了导致我们在这里要检验的假设的信息：遗传和非遗传 来自TP53基因的生物标记物单独或结合其他异常可以预测临床行为。 在这个应用中，我们提出了三个目的来研究这些可疑的生物标记物的潜力。在目标1中，我们 将决定IPI和免疫组织化学生物标记物(包括P53)的组合是否为 临床上预测DLBCL预后的模型比单独使用IPI更准确。在目标2中，我们将确定 TP53 3‘非翻译区的单核苷酸变异和Tp53基因突变的组合是否 TP53编码序列是判断DLBCL预后的生物标志物。在目标3中，我们将确定循环 MiRNAs和游离DNA是DLBCL预后和复发检测的生物标志物。实现目标 本提案将揭开DLBCL中新的非编码生物标记物的面纱，从而开启一种新的未被探索的 研究范围广泛的预后、治疗决策和可能的药物开发研究领域 癌症。