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

基本信息

批准号：
10433889
负责人：
KEN H YOUNG
金额：
$ 36.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10433889
关键词：
3&apos Untranslated Regions Aftercare Age Area B-Cell Lymphomas Behavior Biological Markers Cancer Biology Cancer Prognosis Categories 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 Lymphoma cell MYC gene Malignant Neoplasms Malignant lymphoid neoplasm Medical center MicroRNAs Modeling Molecular Mutation Non-Hodgkin&apos s Lymphoma Oncogenic Outcome Pathogenesis Pathway interactions Patients Performance Status Pharmacotherapy Plasma Plasma Cells Prednisone Prognosis Progression-Free Survivals Public Health Recurrence Recurrent disease Refractory Disease Regimen Relapse Residual state Risk Sampling Serum Single Nucleotide Polymorphism Site Survival Rate 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&apos s lymphoma mutant non-genetic novel novel therapeutic intervention novel therapeutics patient stratification predictive modeling prognosis biomarker prognostic prognostic model prognostic significance prognostication relapse prediction rituximab tool treatment response treatment stratification tumor virtual

项目摘要

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.

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国家。一半的 DLBCL 无法通过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)。目前最常用的工具是确定 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、体能状态、和结外疾病部位的数量）。然而，具有相同 IPI 评分的 DLBCL 患者表现出明显的变异性生存率，表明每个 IPI 类别中存在显着的残留异质性。 TP53 基因编码p53肿瘤抑制因子，人类基因组的守护者。 p53 无法正常工作在大多数人类肿瘤中，仅约 50% 的肿瘤是由于 TP53 基因突变直接导致其失活人类肿瘤。 p53 通路的失调对于淋巴样疾病的发病机制很重要包括 DLBCL 在内的恶性肿瘤，但约 20% 的 DLBCL 中出现 TP53 编码序列突变患者。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，我们获得了导致我们建议在这里测试的假设的信息：遗传和非遗传 TP53 基因的生物标志物单独或与其他异常结合可以预测临床行为。在此应用中，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）的组合是否为与单独的 IPI 预测 DLBCL 预后相比，该模型在临床上更准确。在目标 #2 中，我们将确定 TP53 3'非翻译区的单核苷酸变异和突变的组合是否 TP53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示 DLBCL 中的新型非编码生物标志物，从而开辟一个新的、未经探索的领域预后、治疗决策以及可能的药物开发研究领域癌症。