Estrategia para la identificación y caracterización funcional de nuevas translocaciones cromosómicas en cáncer

Resumen

Cancer is a heterogeneous group of diseases whose initiation and progression is determined by the appearance of genetic and epigenetic alterations. Chromosomal instability in particular is one of the signatures of haematological malignancies. Therefore, genomic rearrangements like translocations, that cause the appearance of chimeric transcripts or deregulated expression of genes, are common mechanisms in tumor cells. Molecular characterization of fusion sequences has shown that, at least for a few genes, the breakpoints tend to cluster in specific regions. As result, the distribution of the breakpoints follows a non-random pattern, with few sites where the breakpoints are more frequent than would be expected by chance. Although several studies have shown the role of nucleotide motifs and local characteristics of the sequences as the cause of such non-random distribution, the relevance of the functional factors in defining the position of the breakpoints involved in chromosomal translocations has not yet been tested experimentally. In order to explain the non-random distribution of breakpoints in chromosome translocations we have studied functional factors such as protein domains as well as the need to maintain an intact reading frame in the fusion product. Until recently, fusion genes have been associated almost exclusively with hematological malignancies and mesenchymal tumors. Recent studies have shown, however, that fusions are also responsible for the pathogenesis of certain epithelial cancers, such as prostate cancer and NSCLC. For this reason we hypothesize that there must exist other rearrangements causing fusion genes in other solid tumors, but its description has not been possible until now because of methodological problems. Therefore, we have searched for novel fusion genes search using a new methodology based on exon microarrays.