Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling

Abstract

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

Diagnostic, progressive and prognostic performance of m6A methylation RNA regulators in lung adenocarcinoma

“…Thus, we inferred that those regulators were likely only effective in some types of LUAD, while the specific reasons required following elucidation. Besides, it was note-worthy that YTHDF2 was merely reported to be involved with TP53 in peripheral T-cell lymphoma and gastric cancer yet [66,67]. YTHDF1 was functionally interactional with TP53 in gastric cancer [67].…”

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

“…represented the next most commonly altered gene class, identified in 40% of cases and restricted to CD4+, CD4+/CD8+, and CD4-/CD8-cases. Mutations in epigenetic modifiers, which are believed to be early events in lymphomagenesis 32,33 and known to cooperate with other mutations in fostering neoplastic transformation 33,34 , have also been reported in diverse T-cell malignancies 33,35 . However, in contrast to other T-cell lymphomas 36 , IDH1/2 mutations were not observed in any ITLPD.…”

Clinical utility of target capture‐based panel sequencing in hematological malignancies: A multicenter feasibility study

“…20 Using tumor cells and matched normal tissue, mutation calling was performed using the Genomon2 pipeline (https://genom on.readt hedocs.io/ja/lates t/), as previously described. 5,21 Putative somatic mutations with (i) a Fisher exact test P-value of <.01, (ii) a VAF in the tumors of >.05, (iii) a sequencing depth in the tumor of ≥50 were adopted, and filtered by excluding (i) synonymous SNVs or noncoding variants and (ii) variants only present in unidirectional reads. The remaining variants were interrogated for evidence that they were present at significantly higher VAFs than expected for errors (P ≤ 10−3), for which the statistical significance was evaluated by empirical Bayesian mutation calling, as previously described.…”