Background: The aggressive clinical behavior of mantle cell lymphoma (MCL) is mainly attributed to the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, a certain degree of clinical/biological heterogeneity has been reported. Aims: To identify MCL subsets with peculiar clinical/biological features in the context of a cohort of homogeneously treated MCL patients. Methods: The study used gene expression profiling (GEP) and quantitative real-time PCR (qRT-PCR) validations in peripheral blood (PB, n=46) and formalin fixed paraffin embedded (FFPE, n=42) samples from 82 MCL cases enrolled in the Fondazione Italiana Linfomi (FIL)-MCL-0208 randomized clinical trial (high-dose therapy followed by autologous transplantation). Results: i) Unsupervised and supervised analyses. GEP from 27 PB samples were analyzed by principal component analysis (PCA) and divided in two subgroups named PCA1 (14 cases) and PCA2 (13 cases). Supervised analysis, according to PCA classification, identified a gene expression signature of 902 probes (700 up-regulated). Gene Set Enrichment Analysis (GSEA) demonstrated a significant enrichment of five B Cell Receptor (BCR)-related gene sets, these genes being constitutively over-expressed in PCA2 samples. ii) Identification of a “PCA2-type” gene signature. By merging the lists of differentially expressed genes and the BCR signaling related genes according to GSEA, a group of 14 genes, all overexpressed in PCA2 cases, was obtained. Among these genes, 6 genes, AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK, were selected for further validations. iii) Generation of a 6-gene prediction model. These 6 genes were analyzed by qRT-PCR and utilized to generate a prediction model by using 17 cases as training cohort and 10 cases as validation cohort (all from PB samples). By this approach, 10/10 cases of the validation cohort were correctly assigned according to the PCA2/PCA1 classification. qRT-PCR was then utilized to classify 19 additional cases (10 PCA2 cases) not employed in GEP. Overall, in the 46 cases, 23 cases were classified as PCA2 by the GEP/qRT-PCR approach. iv) Clinical/biological correlations. No
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