Peripheral T-Cell Lymphoma. Molecular Heterogeneity Revealed by Integrative Genomic Analysis.

Peripheral T-cell lymphoma (PTCL) has been the subject of a relatively limited number of studies to elucidate the molecular pathogenesis. As a result, molecular classification of PTCL is still to be developed, targeted drugs are in very early development and clinical outcome is dismal. Recently, new technologies in genomic analysis have offered the opportunity to improve the knowledge regarding microRNA and gene expression signatures in T-cell lymphoma as well as the potential of microRNAs as prognostic markers in this disease.

The study included a group of 22 patients with PTCL along with 7 reactive lymph nodes (LN) as controls. The global microRNA and gene expression profiles were examined using a commercially available Agilent platform. To identify microRNAs differentially expressed in PTCL versus LN samples and between different subgroups of PTCL, we used the significance analysis of microarrays (SAM) protocol and permutation tests (10,000 permutations). For analysis of pathways associated with PTCL pathogenesis, a gene set enrichment analysis (GSEA) was performed. Results were validated in an additional set of paraffin embedded samples.

A signature composed of 80 microRNAs was found to be differentially expressed in PTCL compared with LN, including the let-7 family, mir-10, mir-15, mir-16 and miR-101 (p<0.0001). Gene expression profiling (GEP) revealed twelve pathways significantly enriched in malignant tissue (FDR<0.1), including the ERK, EGF, CDK5, MET and cytokine induced signaling cascades. GEP data were analyzed trying to correlate the lymphoma cases with the signatures of different T-cell subpopulations including TH1, TH2, T-reg, TH17, TFH and cytotoxic T-cells. The analysis of lymphoma samples revealed a group of 5 cases with a null phenotype lacking any resemblance to normal T-cell subpopulations. These patients were CD4, CD8 double negative and had poorer prognosis than patients with tumors expressing T-cell differentiation markers. We compared microRNA and gene expression profiles of the cases with null-phenotype vs. differentiated-phenotype and found that the former group expressed oncogenic microRNAs, such as the miR-17-92 cluster (Oncomir-1) and miR-181 family. In addition, a set of 27 microRNAs was lost in the null-phenotype group (FDR<0.0001). These included miR-223, miR-100, let-7b, let-7c, miR-145, miR-195 and miR-497 which target genes of the insulin like growth factor 1 (IGF-1) pathway and oncogenic Ras family, signaling cascades that have been shown to function as potent proliferation stimuli. Consistently with the results as outlined above, GSEA analysis demonstrated RACCYCD (Ras and Rho), IGF1, Wnt and cell cycle regulation pathway enrichment in the null-phenotype group. In contrast, NK/T, T-cytotoxic, inflammatory cytokine, NF-κB and T-cell receptor (TCR) pathways were significantly upregulated in the differentiated group (FDR<0.1).

Molecular analysis of PTCL, facilitated by the comparison with normal T-cell subpopulations, revealed the existence of a null-phenotype PTCL, characterized by aggressive behavior and expressing a microRNA oncogenic signature. This research suggests possible and novel roles for microRNAs in the diagnosis and pathogenesis of T-cell lymphoma.

No relevant conflicts of interest to declare.