CDKN2A
生物
癌症研究
外周T细胞淋巴瘤
PI3K/AKT/mTOR通路
关贸总协定3
PTEN公司
淋巴瘤
遗传学
基因
T细胞
信号转导
免疫学
转录因子
免疫系统
作者
Tayla B. Heavican,Alyssa Bouska,Jiayu Yu,Waseem Lone,Catalina Amador,Qiang Gong,Wei Zhang,Yuping Li,Bhavana J. Davé,Maarja-Liisa Nairismägi,Timothy C. Greiner,Julie M. Vose,Dennis D. Weisenburger,Cynthia M. Lachel,Chao Wang,Kai Fu,Jadd M. Stevens,Soon Thye Lim,Choon Kiat Ong,Randy D. Gascoyne
出处
期刊:Blood
[Elsevier BV]
日期:2019-02-20
卷期号:133 (15): 1664-1676
被引量:226
标识
DOI:10.1182/blood-2018-09-872549
摘要
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.
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