Peripheral T-cell lymphoma: molecular profiling recognizes subclasses and identifies prognostic markers

Abstract

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of around 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma, AITL; PTCL-with T follicular helper phenotype, PTCL-TFH; PTCL-not otherwise signified, PTCL-NOS) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH and PTCL-NOS. The main differences between the three nodal PTCL classes involved the RHOAG17V mutations (p<0.0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases, but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these three categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

“…[251][252][253] Multiple studies have reinforced the notion that these 3 entities are unified by a common genetic landscape in addition to a TFH immunophenotype. 251,252,254 Loss-of-function mutations in genes that regulate DNA and histone methylation, specifically TET2 (present in about 80%), and/or DNMT3A (present in 30%-40%) of the patients, and several lines of evidence, indicate that AITL in many instances develops on a background of clonal hematopoiesis. Other alterations include a highly recurrent RHOA G17V hotspot mutation, mutations in IDH2 R172 , and mutations in genes involved in TCR signaling.…”

Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

“…3C ). Consistent with the development of an AITL condition, the transcriptome of the lymphoma samples obtained from Trp53 ER/ER ; Vav1 ΔC/ΔC mice includes the upregulation of AITL‐specific genes such as Bcl6 , Maf , Il21 , Pdcd1 , and Icos [ 46 ] (Fig. 3D ).…”

Pathologic and molecular insights in nodal T-follicular helper cell lymphomas

“…Similarly to FTCL, gene expression studies show that TFH lymphoma, NOS clusters closer to AITL than PTCL-NOS (5,76). The mutational profile of TFH lymphoma, NOS, seems similar to AITL mutations in TET2, DNMT3A, and RHOA G17V (5,56,76). IDH2 R172 mutation is characteristic of AITL, although it can rarely be seen in TFH lymphoma, NOS (90).…”

“…Partial expression of CD30 by the tumor cells is not unusual, and aberrant expression of CD20 by the lymphoma cells has also been reported (53). High expression of CD20 has been reported to be associated with a better overall survival (54)(55)(56). The use of follicular dendritic cell markers (e.g., CD21, CD23, or CD35) is helpful to assess for perivascular expansion of FDCs.…”

“…AITL frequently shows a distinctive mutational profile with mutations involving RHOA G17V (50-70%), TET2 (40-80%), IDH2 R172 (20-45%) and DNMT3A (20-30%) ( Table 2 ) ( 5 , 55 , 56 ).…”