PTCL have been the subject of a limited number of GEP studies14–22 59 60
(). In particular, Tracey et al
Lamant et al16
and de Leval et al17
focused on mycosis fungoides, ALK-positive and -negative ALCLs, and AITL, respectively. In contrast, Martinez-Delgado et al14
and Ballester et al15
analysed large collections of PTCL of the NOS, AITL and ALCL types. However, their studies suffered limitations that varied from the usage of chips with a restricted number of genes14 15
to the lack of a reliable normal counterpart for comparison.14
Martinez-Delgado et al14
reported that PTCL/NOS corresponded to a heterogeneous group of tumours whose GEP was difficult to interpret due to the amount of infiltrating reactive cells. According to those authors, the only clinically relevant information provided by GEP pertains the NF-κB gene expression level (see below).14
Ballester et al15
reported that GEP could discriminate among PTCL of the NOS, AITL and ALCL types, although NOS did not share a single profile. Using a multiclass predictor, the authors separated their cases into three molecular subgroups: U1, U2 and U3. However, the corresponding signatures might have been, at least in part, influenced by reactive components, as suggested by the fact that, for instance, the U3 subgroup consisted almost entirely of histiocyte-rich tumours.
The main studies dealing with gene expression profiling of peripheral T cell lymphomas
published a GEP study based on the analysis of 28 PTCL/NOS, all corresponding to lymph node biopsy samples containing an amount of neoplastic cells exceeding 70% value of the whole examined population. The mRNA extracted from these cases was hybridised on the HG U133 2.0 Plus gene chip. The results obtained were compared with those of six AITL, six ALCL (two ALK-positive and four ALK-negative) and 20 samples of normal T lymphocytes, which were purified from the peripheral blood and tonsil and corresponded to the main T cell subsets (CD4+, CD8+, resting and activated). Such a study significantly differed from most previous reports14 60
in terms of methodology and selection criteria. In addition, for the first time it provided the rationale for possible targeted therapies in PTCL/NOS by offering clear evidence of their ex vivo effectiveness.
In particular, the GEP we detected20
indicated that PTCL/NOS are distinct from normal T and B lymphocytes and are more closely related to activated rather than resting T cells. As in normal mature T lymphocytes, it was possible to identify two main subgroups of PTCL/NOS, with GEPs related to either CD4 or CD8 elements. Notably, this characteristic did not reflect the expression of CD4 and CD8 molecules.
In addition to histogenetic information, our analysis20
provided several insights into the functional alterations of PTCL/NOS. A careful comparison of PTCL/NOS with the closest normal counterparts revealed the systematic deregulation of 155 genes controlling functions that are typically damaged in malignant cells, such as matrix remodelling, cell adhesion, transcription, proliferation and apoptosis. In particular, our findings might explain the dissemination pattern of PTCL/NOS, with frequent extranodal and bone-marrow involvement and spread to peripheral blood,1
by showing the upregulation of FN1
, and COL12A1
(ie, genes that promote local invasion and metastasis in different types of human cancer).61–63
In addition, it revealed the deregulation of genes involved in apoptosis (eg, MOAP1
and chemoresistance (such as CYR61
Immunohistochemistry provided in situ validation of the genomic data by showing correspondence between mRNA and protein expression, as seen, for example, with GEP, PDGFRα (see ) and BCL10. In addition, by comparison with normal tissues, immunohistochemistry allowed the identification of staining patterns corresponding to the synthesis of ectopic or paraphysiological products by neoplastic cells. Finally, the phenotypic test highlighted the possibility that some of the results obtained by GEP may depend on non-neoplastic components present in the analysed sample, as seen for Caldesmon.
In the course of the same study, we found that all ALCLs tended to cluster together – irrespective of their ALK positivity or negativity – showing a signature distinct from those of PTCL/NOS and AITL.20
More recently, we succeeded in identifying a gene signature discriminating between PTCL/NOS and AITL ().22
In addition, the observed AITL global profile strengthened its derivation from the follicular T helper lymphocyte (FTH
L), as originally proposed by Rüdiger et al83
and de Leval et al
Among upregulated genes, were those encoding for CXC13, PD1 and vascular endothelial growth factor (VEGF).
Figure 2 Peripheral T cell lymphoma, not otherwise specified (PTCL/NOS), and peripheral T cell lymphoma, angioimmunoblastic type (AILT), can be distinguished according to their gene expression profile. Eighty-three differentially expressed genes are plotted in (more ...)