4.7 Article

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

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BLOOD
卷 133, 期 15, 页码 1664-1676

出版社

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-09-872549

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资金

  1. City of Hope Lymphoma Specialized Programs of Research Excellence grant [P50 CA107399]
  2. National Institutes of Health (NIH) National Cancer Institute (NCI) [P30 CA033572]
  3. NIH NCI Eppley Cancer Center Support grant [P30 CA036727]
  4. NIH National Center for Research Resources [1S10RR027754-01, 5P20RR016469, RR018788-08]
  5. NIH National Institute for General Medical Science [8P20GM103427, GM103471-09]
  6. Oncosuisse grant [KLS-02403-02-2009]
  7. Anna Lisa Stiftung
  8. GELU Foundation
  9. Leukemia and Lymphoma Society [TRP-6129-04]
  10. NIH NCI [UH2 CA206127 02, P01 CA229100 01]
  11. NIH NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) [II 5 UO1 CA157581-01]
  12. NIH NCI Specialized Programs of Research Excellence [1P50 CA136411-01 01A1 PP-4]
  13. City of Hope internal funds
  14. Singapore Ministry of Health's National Medical Research Council
  15. Tanoto Foundation
  16. New Century International Pte. Ltd.
  17. Ling Foundation
  18. Singapore National Cancer Centre Research Fund
  19. Oncology Academic Clinical Program (ONCO-ACP) Cancer Collaborative Scheme
  20. 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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