Molecular cytogenetic characterization of chromosomal changes in multiple myeloma new insights into pathogenesis and diagnosis

• Autores: Borja Saez
• Directores de la Tesis: María Jose Calasanz Abínzano (dir. tes.), Reiner Siebert (codir. tes.)
• Lectura: En la Universidad de Navarra ( España ) en 2006
• Idioma: español
• Tribunal Calificador de la Tesis: Jordi Sierra Gil (presid.), Felipe Prósper Cardoso (secret.), Juan Cruz Cigudosa García (voc.), José A. Martínez Climent (voc.), Anne Hauch (voc.)
• Materias:
  • Ciencias de la vida
    • Genética
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• Resumen

  • Genetic study in hematological malignancies, such as leukemias, has led to the identification of biological disti net disease subtypes characterized by specific genètic changes, resulting in varying responses to treatment and cl i ni cal outeomes. Conversely, progress in múltiple myeloma (mm) has been slow and the genètic background of the disease remains widely unknown. Nevertheless, a number of recurrent chromosomal aberrations have been reported in mm, some of which appear to be associated with an unfavorable outcome. Therefore, the overall goal of the present work is to give insights into the cytogenetic background of MM and to develop accurate approaches for the cytogenetic diagnosis of this heterogeneous disease. Here, application of multivariate statistical analysis towards MM abnormal karyotypes has permitted the description of a novel classifi catión of MM based on the presence of specific chromosomal abnormali ties. Nevertheless, a definitive molecular classifi catión will require revisión and refinement to reflect further insights as additional initiating and progression genetic events are identified. Therefore, in order to describe novel genètic events in MM, spectral karyotyping (SKY) and fluorescent in situ hybridization (fish) were applied to a series of MM with complex karyotypes. These approaches permitted the detecti on of novel chromosomal aberrations in MM, which implication in MM pathogenesis needs to be investigated. However, these results make us presume that the use of these techniques in combination with other novel approaches based on micro-arrays may help to identify novel genètic abnormalities implicated in MM pathogenesis. Finally, novel tools, based on multicolor FISH and multicolor FICTION (Fluorescence Immunophenotyping and interphase Cytogenetics as a Tool for the investigation of Neoplasms), were designed for the detección of those abnormalities associated with an unfavorable outcome in MM. Analyses of primary MM cases and celi lines with these specific assays confirmed the performance and validity of the techniques and established its diagnòstic power. Therefore, these techniques might permit the early detecti on of genetic changes, evaluation of follow-up and monitoring of mi nimal residual disease in MM patients.