Research Project
10296755
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.
