Obiettivo
New diagnostic tools have been developed for the detection of tumor associated chromosomal aberrations as a spin off from improved physical maps in the corresponding regions of the human genome. Fluorescence in situ hybridization (FISH) protocols are especially designed to meet clinical requirements. Thus, sets of deoxyribonucleic acid (DNA) probes have been generated that allow the routine diagnosis of the most common cytogenetic abnormalities. Furthermore, multicolour FISH protocols have been established for the simultaneous diagnosis of the most important chromosomal changes in certain types of leukemias.
The practicability and resolution of various new techniques have been assessed for high resolution mapping by FISH and their application for the generation of a physical map of 17q11. Specific chromosomal aberrations associated with leukamias have been characterized and protocols have been optimized to detect these aberrations by FISH using genomic DNA probes; these chromosomal aberrations include translocations and deletions involving 11q23, translocation t(9;22)(q34;q11) and trisomy 12 in lymphoid leukemias, as well as translocations t(9;22)(q34;q11), t(8;21) and t(3;21) in myeloid leukemias. New recurrent aberrations are being detected in chronic lymphocytic leukemias and DNA probe sets are being optimized for their clinical diagnosis; these include deletion of the RB-1 gene and the TP53 gene. An assessment of the practicability of multicolour probe sets in haematological diseases has been carried out and further development of the new approach of comparative genomic hybridization (CGH) has taken place.
In situ hybridization has been a major means for physical mapping of nucleic acid probes. By the combination of newly developed protocols for nonisotopic in situ hybridization and digital imaging microscopy, it has been demonstrated that DNA probes can be mapped along prometaphase chromosomes with speed and precision (Lichter et al., Science 247, 64-69, 1990), achieving a resolution in the 1 Mbp range. In order to improve the mapping resolution, highly elongated chromosomes prepared by various techniques (eg by premature chromosome condensation (PCC) or by certain drug treatments) will be used. This approach will be tested using multiple cosmid probes previously mapped to chromosomes 11 and 17.
The concept of mapping probes relative to each other by comparing many average distances between probe signals in interphase nuclei has been reported in the literature. However little is known about differential and, for example, cell type specific condensation of chromatin in the investigated range of 10 to 1000 kb. In order to test interphase mapping as a general approach, the above mentioned cosmid probes will also be mapped using interphase nuclei preparations. These data will be compared to the mapping by using various preparation techniques.
Sets of DNA probes ordered along chromosomes will be of great potential in detecting chromosomal aberrations. In particular, probes specifically delineating a genomic segment by in situ hybridization with high efficiency, will allow the development of new diagnostic tools to detect numerical and structural aberrations. In order to develop such new tools three regions of the human genome will be analyzed: chromosomal aberrations involving 11q and 13q using chromosomes from chronic lymphoproliferative and acute leukaemia patients, and structural aberrations in 17p mainly using material from patients with Miller-Dieker syndrome, Smith-Magenis syndrome or Charcot-Marie-Tooth disease.
In order to detect translocations and (even submicroscopic) deletions performing a single simultaneous hybridization-multicolour detection experiment sets of differentially labelled probes will established. For further characterization additional probe sets covering subregions of the investigated area will be designed. These approaches will be carried out not only on metaphase chromosomes but also in interphase nuclei to develop protocols for the detection of translocations and small deletions in tissues which are not accessible by conventional cytogenetic techniques.
The probe sets will be designed and tested using cytogenetically characterized chromosomes with structural alterations of 11q followed by a blind study with material from the same kind of leukaemia patients. Similarly, single probes and combinations of probes which unambiguously detect alterations, in particular microdeletions, in 17p will be devised using patient cell material.
Campo scientifico (EuroSciVoc)
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
- scienze naturali scienze biologiche biochimica biomolecole acidi nucleici
- scienze naturali scienze biologiche genetica DNA
- scienze mediche e della salute medicina clinica oncologia leucemia
- scienze naturali scienze biologiche genetica cromosomi
- scienze naturali scienze biologiche genetica genomi
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Coordinatore
69120 Heidelberg
Germania
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