Caratterizzazione molecolare della sindrome di Sezary e possibili risvolti prognostico-terapeutici.
Creators: name: SAPORITI, GIORGIA NATASCIA
Publisher: name: Universit� degli Studi di Milano
Year: 2013

description: S�zary Syndrome (SS) is an aggressive type of cutaneous CD4+ T-cell lymphoma characterized by erythroderma, generalized lymphadenopathy and presence of malignant T cells in peripheral blood. Patients with SS have a generally poor median survival (2-4 years), with allogeneic stem cell transplantation as the only curative treatment option. Genome-wide analysis of chromosomal alterations represents a current powerful tool to investigate pathophysiology in hematological malignancies, possibly leading to development of new therapeutic agents. A recent important study reported gain of 17q22-25 and 8q22-24, as well as loss of 17p13 and 10q25 as characteristic genomic aberrations in SS. 
In this study, by array-based comparative genomic hybridization (a-CGH), we aimed to further explore genomic alterations in 40 patients with S�zary Syndrome (SS) referred to our Institution. The patient series included 16 males and 24 females, with a median age of 67 years (range 29 to 86). At diagnosis, 5 patients were in stage IIIB, 28 in stage IVA1 and 7 in stage IVA2. Flow cytometry analysis unveiled typical CD4+/CD7�/CD26- lymphocytic immunophenotype, while molecular analysis showed clonal rearrangement of T-cell receptor beta and/or gamma chains in all patients. At the time of blood samples collection, 57% of patients received no chemotherapy. Lymphocyte count was higher than 3000/mcL in 33% of patients. Elevated LDH levels were observed in 30%. 
Genomic DNA was isolated from peripheral blood mononuclear cells of 10 patients and from CD4+/CD14- cells of 30 patients, selected by an immunomagnetic method. Quantity and quality of all gDNA samples were assessed using UV- VIS spectrophotometry and agarose gel electrophoresis. Genome-wide array-based comparative genomic hybridization (aCGH) was performed using the Agilent Human Genome CGH Microarray Kit 4x44K. Copy number profiles from CGH arrays were compared using Integrative Genome Viewer. 
Most frequently observed recurrent copy number alterations involved gains in chromosomes 7, 8 and 17 and losses in chromosome 10, 17 and 19. In particular, chromosomal gains involved 7q22.1 in 40% of patients, 8q24.2-8q24.3 in 55% (with amplification of the MYC oncogene in 45%), while chromosomal losses involved 10p11.22 in 45% of patients, 10q25.1 in 65%, 10q24 (involving NFkB2 gene) in 63%, and 19p13.3 (involving the cell growth/apoptosis regulating GADD45B gene) in 40%. With regard to chromosome 17, we observed loss of region 17p13.1 (containing the TP53 gene) in 75% of cases, whereas a gain in 17q21 (harbouring genes coding for STAT3, STAT5A e STAT5B) was documented in 64% of patients. Worth mentioning, 52% of cases showed both losses in the p arm and gains in the q arm within chromosome 17. 
In summary, our results partially confirmed those previously reported with regard to alterations in chromosomes 7, 8, 10 and 17, resulting in amplification of oncogenes and deletion of tumor suppressor genes. We also observed genome alterations associated with activation of the signal transduction JAK/STAT pathway, possibly involved in SS malignant phenotype. Further genome alterations emerged in this study, such as those in chromosome 7 and 19, are also worth investigating for their possible pathophysiological meanings.