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Blood. 2019 Apr 11;133(15):1664-1676. doi: 10.1182/blood-2018-09-872549. Epub 2019 Feb 19.

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

Author information

1
Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
2
Department of Pathology, City of Hope National Medical Center, Duarte, CA.
3
Human Genetics Laboratory, University of Nebraska Medical Center, Omaha, NE.
4
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
5
Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE.
6
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada.
7
Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.
8
Département de Pathologie, Université Paris-Est, Hôpital Henri-Mondor, INSERM U955, Créteil, France.
9
Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
10
Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
11
European Institute of Oncology, Milan/Bologna University School of Medicine, Bologna, Italy.
12
Department of Internal Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, MI.
13
Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
14
Institute of Pathology, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
15
Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
16
Hematopathology Unit, Hospital Clinic, Barcelona, Spain.
17
Department of Pathology, University of Arizona, Tucson, AZ.
18
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
19
Oregon Health Sciences Center, Portland, OR.
20
Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY.
21
Università della Svizzera Italiana, Istituto Oncologico di Ricerca, Bellinzona, Switzerland; and.
22
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

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.

PMID:
30782609
PMCID:
PMC6460420
[Available on 2020-04-11]
DOI:
10.1182/blood-2018-09-872549

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