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Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

ABSTRACT: Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

SUBMITTER: Heavican TB

PROVIDER: S-EPMC6460420 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

Heavican Tayla B TB Bouska Alyssa A Yu Jiayu J Lone Waseem W Amador Catalina C Gong Qiang Q Zhang Weiwei W Li Yuping Y Dave Bhavana J BJ Nairismägi Maarja-Liisa ML Greiner Timothy C TC Vose Julie J Weisenburger Dennis D DD Lachel Cynthia C Wang Chao C Fu Kai K Stevens Jadd M JM Lim Soon Thye ST Ong Choon Kiat CK Gascoyne Randy D RD Missiaglia Edoardo E Lemonnier Francois F Haioun Corinne C Hartmann Sylvia S Pedersen Martin Bjerregård MB Laginestra Maria Antonella MA Wilcox Ryan A RA Teh Bin Tean BT Yoshida Noriaki N Ohshima Koichi K Seto Masao M Rosenwald Andreas A Ott German G Campo Elias E Rimsza Lisa M LM Jaffe Elaine S ES Braziel Rita M RM d'Amore Francesco F Inghirami Giorgio G Bertoni Francesco F de Leval Laurence L Gaulard Philippe P Staudt Louis M LM McKeithan Timothy W TW Pileri Stefano S Chan Wing C WC Iqbal Javeed J

Blood 20190219 15

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targe ...[more]

PMID: 30782609

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Project description:PurposePeripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis.Experimental designWe used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments.ResultsEffector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction.ConclusionsUnique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.

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Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

Publications

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

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