Estudio del genoma y del transcriptoma en las fases evolutivas de las gammapatías monoclonales
[EN] Epidemiological studies have shown that virtually all multiple myeloma are preceded by a premalignant phase. In this regard, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (MMQ) are considered premalignant and asymptomatic entities differ significantly in the rate of progression to symptomatic MM. Despite their radically different clinical behavior, the three entities share the same neoplastic cell apparently, which is a plasma cell (PC) and aberrant clonal. Cytogenetics and fluorescence in situ hybridization (FISH) have failed to identify abnormalities characteristic of each developmental stage. However, this could be due to either the lack of a specific genetic stamp of each developmental stage of monoclonal gammopathies, or they have not been used and the analysis tools suitable for your search. Therefore, the combination of classical cytogenetic techniques as HISF advanced genomic techniques and high resolution for exploring the status of the genome and transcriptome, could be decisive when further genetic mechanisms that trigger the transformation of premalignant entities to active MM. Furthermore, in the developmental stages of monoclonal gammopathies exists an intermediate entity between MGUS and MM is the MMQ, characterized by a risk of progression to symptomatic myeloma approximately ten times greater than the GMSI. Within the MMQ defined a group at high risk of progression to symptomatic MM (MMQ-AR). The standard treatment is abstinence MMQ to progression to symptomatic MM. Our group is leading a clinical trial (QuiReDex) to determine whether treatment with lenalidomide plus dexamethasone (LenDex) MMQ-AR in prolonging the time to progression. The opportunity to study the genome and transcriptome of a unique group of patients carefully defined from the clinical point of view, could help determine if there are genetic basis justifying a different clinical outcome in these patients. Finally, treatment of patients LenDex after randomisation in QuiReDex assay, it is for the treatment arm, allow us analyze the transcriptome of non-hematopoietic tumor cells and thus, further both the mechanisms of action of lenalidomide derived from its effects on the microenvironment and the mechanisms of toxicity profile. With this background we have set the following objectives: 1. Analyzed by fluorescence in situ hybridization frequency of recurrent genetic abnormalities and quantify the proportion of plasma cells containing abnormalities in these three developmental stages of monoclonal gammopathies. 2. Studying the gains and losses of chromosomal material, as well as losses of heterozygosity in different developmental stages of monoclonal gammopathies: MGUS, MMQ and symptomatic MM. 3. To study the gene expression profiles of MGUS, the MQM and the GM, in order to identify similarities and differences that help explain the different evolution of the three entities. 4. To investigate whether genomic changes and gene expression observed in a group of patients with high-risk MMQ included in the clinical trial QuiReDex, influence their clinical course. 5. Evaluate the impact of treatment with lenalidomide / dexamethasone on the transcriptome of hematopoietic cells in the bone marrow myeloma. The main conclusions of our work are as follows: 1. The study of monoclonal gammopathies by fluorescence in situ hybridization confirmed that IGH translocations, deletions of 13q and 17p, and gains of 1q are present from the early stages of neoplastic transformation (MGUS). However, the progression from MGUS to MM MMQ and finally leads to an increased number of plasma cells genetically abnormal. 2. Using techniques of high resolution genomic analysis, such as arrays of SNPs, show that, despite the GM has more chromosomal abnormalities and loss of heterozygosity (LOH), the transition from MGUS to MM is not associated with given a chromosomal abnormality, but rather with a clonal expansion of genetically aberrant subclones already present in the early stages. 3. The transcriptome of clonal plasma cell MGUS both, as the MQM and MM analyzed by microarray expression shows a significant deregulation of hundreds of genes in the transition from the three developmental stages. Families and more altered gene pathways include apoptosis, NFkB pathway, small nucleolar RNA family (snoRNA) and protein family "zinc finger". 4. As for MM quiescent (MMQ) at high risk of progression to symptomatic MM: a. The profile of chromosomal alterations or LOH not predict the risk of progression of high-risk MMQ. However, the increased expression of several SNORD correlates with shorter time to the development of symptoms CRAB. b. Not found a genetic signature that predicts the response to treatment with lenalidomide plus dexamethasone. c. The plasma cell of high risk MMQ often undergoes clonal evolution at the time of symptomatic MM progression. By contrast, the gene expression profile of the MMQ COP at the time of the progression is not modified. d. Lenalidomide plus dexamethasone in high risk MMQ not alter the expression profile of non-hematopoietic tumor cellularity of bone marrow.
mieloma múltiple, Tesis y disertaciones académicas, Universidad de Salamanca (España), Academic dissertations, Citogenética, Hematología, cytogenetic, Hematology
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