@article{ba529b3c7b4c4a74950e34114dab0fb7,
title = "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 IDH2R172 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.",
author = "Heavican, {Tayla B.} and Alyssa Bouska and Jiayu Yu and Waseem Lone and Catalina Amador and Qiang Gong and Weiwei Zhang and Yuping Li and Dave, {Bhavana J.} and Nairism{\"a}gi, {Maarja Liisa} and Greiner, {Timothy C.} and Julie Vose and Weisenburger, {Dennis D.} and Cynthia Lachel and Chao Wang and Kai Fu and Stevens, {Jadd M.} and Lim, {Soon Thye} and Ong, {Choon Kiat} and Gascoyne, {Randy D.} and Edoardo Missiaglia and Francois Lemonnier and Corinne Haioun and Sylvia Hartmann and Pedersen, {Martin Bjerreg{\aa}rd} and Laginestra, {Maria Antonella} and Wilcox, {Ryan A.} and Teh, {Bin Tean} and Noriaki Yoshida and Koichi Ohshima and Masao Seto and Andreas Rosenwald and German Ott and Elias Campo and Rimsza, {Lisa M.} and Jaffe, {Elaine S.} and Braziel, {Rita M.} and Francesco d{\textquoteright}Amore and Giorgio Inghirami and Francesco Bertoni and {de Leval}, Laurence and Philippe Gaulard and Staudt, {Louis M.} and McKeithan, {Timothy W.} and Stefano Pileri and Chan, {Wing C.} and Javeed Iqbal",
note = "Funding Information: The work was supported in part by City of Hope Lymphoma Specialized Programs of Research Excellence grant P50 CA107399 and National Institutes of Health (NIH) National Cancer Institute (NCI) grant P30 CA033572. Partial support is from NIH NCI Eppley Cancer Center Support grant P30 CA036727, NIH National Center for Research Resources grant 5P20RR016469, and NIH National Institute for General Medical Science grant 8P20GM103427 (G.B.). F.B. is supported by Oncosuisse grant KLS-02403-02-2009, Anna Lisa Stiftung, and The GELU Foundation. J.I. is supported by the Leukemia and Lymphoma Society (TRP-6129-04), NIH NCI Eppley Cancer Center Support grant P30 CA036727 and NIH NCI grants UH2 CA206127 02 and P01 CA229100 01. W.C.C. is supported by NIH NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) II 5 UO1 CA157581-01, NIH NCI Specialized Programs of Research Excellence 1P50 CA136411-01 01A1 PP-4, and City of Hope internal funds. C.K.O. is supported by Singapore Ministry of Health{\textquoteright}s National Medical Research Council, the Tanoto Foundation, New Century International Pte. Ltd., the Ling Foundation, Singapore National Cancer Centre Research Fund, and Oncology Academic Clinical Program (ONCO-ACP) Cancer Collaborative Scheme. The University of Nebraska DNA Sequencing Core receives partial support from NIH National Center for Research Resources (1S10RR027754-01, 5P20RR016469, RR018788-08) and NIH National Institute for General Medical Science (8P20GM103427, GM103471-09). Publisher Copyright: {\textcopyright} 2019 American Society of Hematology. All rights reserved.",
year = "2019",
month = apr,
day = "11",
doi = "10.1182/blood-2018-09-872549",
language = "English (US)",
volume = "133",
pages = "1664--1676",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",
}