Anàlisi dels mecanismes moleculars implicats en el desenvolupament i progressió dels limfomes de cèllula B petita

by Fernàndez Pascual, Verònica

SUMMARY: ANALYSIS OF THE MOLECULAR MECHANISMS IMPLIED IN THE DEVELOPMENT AND PROGRESSION OF SMALL B CELL LYMPHOMAS INTRODUCTION: Different molecular mechanisms implied in the development and progression of distinct subtypes of small B cell lymphomas that belong to Non-Hodgkin´s Lymphomas (NHL) have been studied in the present work, specially focusing on Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). MATERIALS AND METHODS: Comparative genomic hybridization (CGH) has been aplied to study the chromosomal alterations of the tumors. Polymerase chain reaction (PCR) and denaturing high performance liquid chromatography (DHPLC) techniques have been performed to detect nucleotide alterations in certain genes; whereas real time quantitative PCR (qPCR) and high density oligonucleotide microarrays have been used to analyse gene expression. RESULTS AND DISCUSSION: The gene expression model composed of the five genes RAN, MYC, TNFRSF10B, POLE2 and SLC29A2 allows the survival prediction of MCL patients with widely disparate clinical outcome and is superior to the immunohistochemical marker Ki-67. The predictor is applicable to fresh frozen and formalin-fixed paraffin-embedded (FFPE) tumor samples. On the other side, the study of the MDM2 gene has shown that increased gene expression correlates with inferior survival in MCL. MDM2 overexpression is associated with copy number gains of the MDM2 locus in single tumors, but not with the recently reported MDM2 promoter SNP309. The study of the death receptors TNFRSF10A and TNFRSF10B has shown that mutations in these genes are uncommon in lymphoid neoplasms, but the presence of certain TNFRSF10A polymorphisms (A1322G in the death domain and C626G in the extracellular binding domain) can contribute to the pathogenesis of these malignancies. The study of early clinical progression in CLL has allowed the identification of a significant modulation of the gene expression of 58 genes, with a particular downregulation of genes that are inhibitors of cell adhesion and motility. On the other side, our results indicate that clinical progression of early stage CLL is associated with karyotype evolution and inactivation of certain tumor suppressor genes.