Defining the biology of HIV-associated aggressive B-cell lymphoma in Southern Africa

南部非洲 HIV 相关侵袭性 B 细胞淋巴瘤的生物学定义

基本信息

批准号：
10478074
负责人：
Katherine Antel
金额：
$ 10.46万
依托单位：
UNIVERSITY OF CAPE TOWN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-27 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478074
关键词：
Advanced Development Africa Africa South of the Sahara African Algorithms Antigens Area Award B-Cell Activation B-Cell Lymphomas B-Lymphocytes BRAF gene Bioinformatics Biological Markers Biological Models Biology Biometry Black Populations Caucasians Characteristics Chronic Classification Clinical Clinical Trials Country DNA Sequence Alteration Dana-Farber Cancer Institute Data Set Development Plans Diagnosis Diagnostic Diffuse Pattern Doctor of Philosophy Ensure Europe Feasibility Studies Future Gene Expression Gene Expression Profile Gene Mutation Genetic Genetic Heterogeneity Genetic Transcription Genetic study Genomics Goals HIV HIV Infections HIV Seronegativity HIV Seropositivity Health Priorities Hematologist Hepatitis B Hepatitis C virus Heterogeneity High Prevalence Hospitals Human Herpesvirus 4 Immunosuppression Income Individual International Laboratories Lymphoma Malignant Neoplasms Mediating Mentors Mentorship Morbidity - disease rate Mutation Non-Hodgkin&apos s Lymphoma Oncogenic Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patient-Focused Outcomes Patients Persons Physicians Play Population Positioning Attribute Recurrence Research Research Design Risk Role Scientist South Africa South African Southern Africa Structure Structure of germinal center of lymph node Taxonomy Therapeutic Time Training Programs Translating Tuberculosis Universities Virus Diseases Work base biomarker-driven career career development co-infection comorbidity cost cost effective diagnostic algorithm diagnostic strategy genomic aberrations high risk improved outcome in vivo inhibitor innovation large cell Diffuse non-Hodgkin&apos s lymphoma medical schools molecular diagnostics mortality next generation sequencing novel novel diagnostics programs skills survival outcome targeted treatment training opportunity treatment response treatment stratification tumorigenesis

项目摘要

PROJECT SUMMARY ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, also among people with HIV, and accounts for roughly one-third of all non-Hodgkin lymphoma (NHL) cases worldwide. The 2008 classification of DLBCL recognized germinal centre B-cell (GCB) and activated B-cell (ABC)/non-GCB subtypes, and also a group that was unclassifiable based on gene expression. More recently, two research groups have independently identified subtypes of DLBCL based on shared genomic aberrations. In both studies, these subtypes differ in respect to pathogenic mechanisms, clinical characteristics, and survival outcomes. Although these studies represent significant advances in our understanding of DLBCL from the US and Europe, there is much work still to be done in describing the genetic patterns of DLBCL in sub-Saharan Africa, especially in patients with HIV. Further understanding of genetic and transcriptional heterogeneity of these lymphomas could inform new diagnostic and treatment approaches that improve outcomes for patients. The scientific goal of this proposal is to establish a biologically informed taxonomy of HIV-associated DLBCL in South Africa. The specific aims are to: (1) Establish genetically and transcriptionally defined subtypes of HIV-associated DLBCL in South Africa; and (2) Establish clinicopathological features of HIV-associated DLBCL associated with these subsets. This proposal is responsive to areas of critical need in South Africa: research that is highly relevant to regional health priorities; and the career development of a local clinician-scientist. These studies also support the long-term goal of developing low-cost diagnostic strategies that guide the treatment of lymphoma in South Africa. The project PI, Dr Katherine Antel, is a clinical hematologist at the University of Cape Town with the career goal of independently conducting research that will improve outcomes for patients with lymphoma. Her PhD work showed that in South Africa there are numerous local obstacles to lymphoma diagnosis and, notably, that within this tuberculosis (TB)- endemic area, patients with lymphoma are at high risk of misdiagnosis with extrapulmonary TB. The diagnostic algorithm developed as part of her research has led to a shorter time-to-diagnosis of lymphoma at Groote Schuur Hospital. A comprehensive career development plan comprising structured activities and mentorship opportunities will enable Dr Antel to continue her career development as a physician-scientist by acquiring advanced skills in 1) next-generation sequencing; 2) bioinformatics; 3) biostatistical approaches for integrating genomics and clinical datasets; and 4) cellular and in vivo approaches to interrogate the effects of novel gene mutations. This K43 award will position her to build an independent program of research in lymphoma that drives innovative diagnostic and therapeutic approaches for patients in southern Africa.

项目概要摘要弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的淋巴瘤类型，在 HIV 感染者中也是如此。约占全球所有非霍奇金淋巴瘤 (NHL) 病例的三分之一。 2008年分类 DLBCL 识别的生发中心 B 细胞 (GCB) 和激活的 B 细胞 (ABC)/非 GCB 亚型，以及根据基因表达无法分类的群体。最近，两个研究小组独立根据共有的基因组畸变鉴定了 DLBCL 的亚型。在这两项研究中，这些亚型的不同之处在于关于致病机制、临床特征和生存结果。虽然这些研究代表了我们对美国和欧洲 DLBCL 理解的重大进展，仍有许多工作要做描述撒哈拉以南非洲地区 DLBCL 的遗传模式，特别是 HIV 患者的遗传模式。进一步了解这些淋巴瘤的遗传和转录异质性可以为新的研究提供信息改善患者预后的诊断和治疗方法。该提案的科学目标是在南非建立 HIV 相关 DLBCL 的生物学分类法。具体目标是 (1) 在南非建立 HIV 相关 DLBCL 的遗传和转录定义亚型；和 (2) 建立与这些亚型相关的 HIV 相关 DLBCL 的临床病理学特征。这个提议响应南非的迫切需求领域：与区域卫生优先事项高度相关的研究；以及当地临床医生科学家的职业发展。这些研究也支持了长期目标制定指导南非淋巴瘤治疗的低成本诊断策略。项目负责人， Katherine Antel 博士是开普敦大学的临床血液学家，其职业目标是独立开展可改善淋巴瘤患者预后的研究。她的博士论文表明，在南方非洲淋巴瘤的诊断存在许多当地障碍，特别是在结核病 (TB) 中 - 在流行区，淋巴瘤患者误诊肺外结核的风险很高。诊断作为她研究的一部分开发的算法缩短了 Groote Schuur 淋巴瘤的诊断时间医院。全面的职业发展计划，包括结构化活动和指导机会将使安特尔博士能够通过收购来继续她作为医师科学家的职业发展 1）下一代测序的高级技能； 2）生物信息学； 3）生物统计学整合方法基因组学和临床数据集； 4) 探究新基因作用的细胞和体内方法突变。该 K43 奖项将使她能够建立一个独立的淋巴瘤研究项目，推动为南部非洲患者提供创新的诊断和治疗方法。