Dataset Information

Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma.

ABSTRACT: Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.

SUBMITTER: Tiacci E

PROVIDER: S-EPMC6634958 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma.

Tiacci Enrico E Ladewig Erik E Schiavoni Gianluca G Penson Alex A Fortini Elisabetta E Pettirossi Valentina V Wang Yuchun Y Rosseto Ariele A Venanzi Alessandra A Vlasevska Sofija S Pacini Roberta R Piattoni Simonetta S Tabarrini Alessia A Pucciarini Alessandra A Bigerna Barbara B Santi Alessia A Gianni Alessandro M AM Viviani Simonetta S Cabras Antonello A Ascani Stefano S Crescenzi Barbara B Mecucci Cristina C Pasqualucci Laura L Rabadan Raul R Falini Brunangelo B

Blood 20180412 22

Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16% ...[more]

PMID: 29650799

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Project description:Jak-STAT, Ras, Notch pathway genes and CD44 are frequently mutated in HIV-associated PBL, and together with transcriptomic features distinguish the disease from closely related B-cell cancers. 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

Dataset Information

Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma.

Publications

Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma.

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