RT Journal Article SR Electronic T1 Genomic Characterization of HIV-Associated Plasmablastic Lymphoma Identifies Pervasive Mutations in the JAK–STAT Pathway JF Blood Cancer Discovery JO Blood Cancer Discov FD American Association for Cancer Research SP 112 OP 125 DO 10.1158/2643-3230.BCD-20-0051 VO 1 IS 1 A1 Liu, Zhaoqi A1 Filip, Ioan A1 Gomez, Karen A1 Engelbrecht, Dewaldt A1 Meer, Shabnum A1 Lalloo, Pooja N. A1 Patel, Pareen A1 Perner, Yvonne A1 Zhao, Junfei A1 Wang, Jiguang A1 Pasqualucci, Laura A1 Rabadan, Raul A1 Willem, Pascale YR 2020 UL http://bloodcancerdiscov.aacrjournals.org/content/1/1/112.abstract AB Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma associated with immunodeficiency in the context of human immunodeficiency virus (HIV) infection or iatrogenic immunosuppression. While a rare disease in general, the incidence is dramatically increased in regions of the world with high HIV prevalence. The molecular pathogenesis of this disease is poorly characterized. Here, we defined the genomic features of PBL in a cohort of 110 patients from South Africa (15 by whole-exome sequencing and 95 by deep targeted sequencing). We identified recurrent mutations in genes of the JAK–STAT signaling pathway, including STAT3 (42%), JAK1 (14%), and SOCS1 (10%), leading to its constitutive activation. Moreover, 24% of cases harbored gain-of-function mutations in RAS family members (NRAS and KRAS). Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations and transcriptional programs. We also found recurrent copy number gains encompassing the CD44 gene (37%), which encodes for a cell surface receptor involved in lymphocyte activation and homing, and was found expressed at high levels in all tested cases, independent of genetic alterations. These findings have implications for the understanding of the pathogenesis of this disease and the development of personalized medicine approaches.Significance: Plasmablastic lymphoma is a poorly studied and extremely aggressive tumor. Here we define the genomic landscape of this lymphoma in HIV-positive individuals from South Africa and identify pervasive mutations in JAK–STAT3 and RAS–MAPK signaling pathways. These data offer a genomic framework for the design of improved treatment strategies targeting these circuits.See related commentary by Küppers, p. 23.This article is highlighted in the In This Issue feature, p. 5