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