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

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.

GATA‐3 in T‐cell lymphoproliferative disorders

“…For example, genomic losses (usually heterozygous) that include relevant tumor suppressor genes, including p53, PTEN, and CDKN2A/B, are observed in~40-50% of GATA-3 PTCL, while genomic losses generally were infrequently observed in T-bet PTCL. 50 Genomic gains involving c-myc were observed in ≈40% of GATA-3 PTCL, and are concordant with the enriched expression of c-myc target genes previously observed in this subset. 19 The loss of relevant tumor suppressor genes, including p53, and amplification of c-myc, may further contribute to the high rate of primary refractory disease observed in GATA-3 PTCL.…”

“…In contrast to the mutational landscape in these epigenetic regulators, significant differences in clinically relevant chromosomal copy number alternations have been observed between GATA‐3 and T‐bet PTCL. For example, genomic losses (usually heterozygous) that include relevant tumor suppressor genes, including p53, PTEN, and CDKN2A/B, are observed in ~40–50% of GATA‐3 PTCL, while genomic losses generally were infrequently observed in T‐bet PTCL . Genomic gains involving c‐myc were observed in ≈40% of GATA‐3 PTCL, and are concordant with the enriched expression of c‐myc target genes previously observed in this subset .…”

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

“…Another mechanism of STAT3 activation is possible through the deregulation of suppressors of the JAK/STAT pathway such as SOCS3 [40] leading to constitutive STAT activation and oncogenesis. In addition, further studies are needed to combine any association with JAK-STAT pathway activation and expression of essential transcription factors such as GATA3 and Tbet, which define new subclasses of PTCL-NOS with prognostic consequences, where GATA3 signatures are associated with worse prognosis [41,42].…”

Approach to nodal-based T-cell lymphomas

“…42 Genomic imbalances are frequent as well; gains of chromosomes 5 and 21 are frequent, especially in IDH2-mutated cases, and copy number losses in genes regulating the PI3K-AKT-mTOR pathway are enriched in IDH2-wild type cases. 43 RNA fusions involving CD28 and ICOS, or rarely CD28 and CTLA4, are detected in a small subset of the patients and are mutually exclusive with CD28 mutations. 44…”