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

项目总结摘要 弥漫性大B细胞淋巴瘤(DLBCL)是最常见的淋巴瘤类型，在艾滋病毒携带者中也是如此， 约占全球所有非霍奇金淋巴瘤(NHL)病例的三分之一。2008年的分类 DLBCL识别的生发中心B细胞(GCB)和活化的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，两个研究小组独立地 根据共同的基因组像差确定DLBCL的亚型。在这两项研究中，这些亚型在 在致病机制、临床特征和生存结果方面。尽管这些研究 代表着我们对美国和欧洲对DLBCL的理解取得了重大进展，仍然有很多工作要做 在描述撒哈拉以南非洲地区，特别是艾滋病毒感染者的DLBCL遗传模式时需要做的工作。 对这些淋巴瘤的遗传和转录异质性的进一步了解可能会为新的 改善患者预后的诊断和治疗方法。这项提议的科学目标是 建立南非HIV相关DLBCL的生物信息学分类学。具体目标是 (1)在南非建立与艾滋病毒相关的DLBCL的基因和转录定义亚型；以及 (2)建立与这些亚群相关的HIV相关性DLBCL的临床病理特征。这项建议 对南非迫切需要的领域作出反应：与区域卫生优先事项高度相关的研究； 以及一位当地临床医生兼科学家的职业发展。这些研究还支持以下长期目标 制定指导南非淋巴瘤治疗的低成本诊断战略。PI项目， 凯瑟琳·安特尔博士是开普敦大学的临床血液学家，她的职业目标是独立 开展将改善淋巴瘤患者预后的研究。她的博士研究表明，在南方 非洲在诊断淋巴瘤方面存在许多当地障碍，特别是在这种结核病(TB)中-- 在流行地区，淋巴瘤患者误诊为肺外结核病的风险很高。诊断 作为她研究的一部分，她开发的算法缩短了Groote Schuur的淋巴瘤诊断时间 医院。全面的职业发展计划，包括有组织的活动和指导 机会将使Antel博士继续她作为内科科学家的职业发展，通过获得 1)下一代测序；2)生物信息学；3)整合生物统计学方法方面的高级技能 基因组学和临床数据集；以及4)细胞和体内方法来询问新基因的影响 突变。这项K43奖将使她能够建立一个独立的淋巴瘤研究项目，以推动 为南部非洲患者提供创新的诊断和治疗方法。

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.