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

Tayla B. Heavican, Alyssa Bouska, Jiayu Yu, Waseem Lone, Catalina Amador, Qiang Gong, Weiwei Zhang, Yuping Li, Bhavana J. Dave, Maarja-Liisa Nairismägi, Timothy C. Greiner, Julie Vose, Dennis D. Weisenburger, Cynthia Lachel, Chao Wang, Kai Fu, Jadd M. Stevens, Soon Thye Lim, Choon Kiat Ong, Randy D. Gascoyne, Edoardo Missiaglia, Francois Lemonnier, Corinne Haioun, Sylvia Hartmann, Martin Bjerregård Pedersen, Maria Antonella Laginestra, Ryan A. Wilcox, Bin Tean Teh, Noriaki Yoshida, Koichi Ohshima, Masao Seto, Andreas Rosenwald, German Ott, Elias Campo, Lisa M. Rimsza, Elaine S. Jaffe, Rita M. Braziel, Francesco d'Amore, Giorgio Inghirami, Francesco Bertoni, Laurence de Leval, Philippe Gaulard, Louis M. Staudt, Timothy W. McKeithan, Stefano Pileri, Wing C. Chan and Javeed Iqbal

Key points

  • Chromosome 5 and 21 gains co-occurred with IDH2R172 mutation in AITL, whereas IDH2 wild-type cases had deletions targeting PI3K-AKT-mTOR.

  • PTCL-NOS molecular subgroups (PTCL-GATA3 and PTCL-TBX21) had distinct genetic aberrations and CDKN2A loss showed prognostic significance.


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 two most frequent categories accounting for more than 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 higher genomic complexity 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 TCR signaling were common in both subgroups. AITL showed lower genomic complexity compared to other PTCL entities, with frequent co-occurring gains of 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.

  • Submitted September 19, 2018.
  • Accepted February 10, 2019.