Journal
BLOOD
Volume 133, Issue 15, Pages 1664-1676Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-09-872549
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Funding
- City of Hope Lymphoma Specialized Programs of Research Excellence grant [P50 CA107399]
- National Institutes of Health (NIH) National Cancer Institute (NCI) [P30 CA033572]
- NIH NCI Eppley Cancer Center Support grant [P30 CA036727]
- NIH National Center for Research Resources [1S10RR027754-01, 5P20RR016469, RR018788-08]
- NIH National Institute for General Medical Science [8P20GM103427, GM103471-09]
- Oncosuisse grant [KLS-02403-02-2009]
- Anna Lisa Stiftung
- GELU Foundation
- Leukemia and Lymphoma Society [TRP-6129-04]
- NIH NCI [UH2 CA206127 02, P01 CA229100 01]
- 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]
- City of Hope internal funds
- Singapore Ministry of Health's National Medical Research Council
- Tanoto Foundation
- New Century International Pte. Ltd.
- Ling Foundation
- Singapore National Cancer Centre Research Fund
- Oncology Academic Clinical Program (ONCO-ACP) Cancer Collaborative Scheme
- NATIONAL CANCER INSTITUTE [ZIABC011006] Funding Source: NIH RePORTER
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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.
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