Mechanisms and Consequences of Chromosomal Instability in Malignant tumours

Abstract: In this thesis, telomere deficiency with subsequent anaphase bridging was found to be associated with chromosomal instability in established colorectal cancer cell lines and in Wilms tumour. In colorectal cancer cell lines, anaphase bridging was observed to generate both numerical and structural chromosomal aberrations and was also associated with the presence of multipolar mitoses. In contrast to cells having undergone anaphase bridging, daughter cells from these multipolar mitotic figures were observed not to form clones in culture, possibly because of the severe aneuploidy which is the result of multipolar mitosis. Chromosomal instability was observed also in colorectal cancer cell lines with mutations in the mismatch repair genes. In Wilms tumour, chromosomal instability was found to be associated with an aggressive tumour phenotype and poor survival. Telomere shortening was more pronounced in the immature tumour components, which could explain the fact that anaphase bridges and multipolar mitoses were only observed in these tumour elements. Because of breakage-fusion-bridge cycles, chromosomal instability is associated with karyotypes with extensive structural chromosomal rearrangements. By applying a combination of subtelomeric FISH, G-banding and multicolour FISH, a high resolution for cytogenetic analysis of tumours with chromosomal instability could be obtained. This combined approached was used also to search for reciprocal translocations leading to fusion genes in Wilms tumour. Although the technique proved efficient, no recurrent reciprocal translocation was found in Wilms tumour. Our results indicate that telomere dependent chromosomal instability is present in both colorectal cancer and Wilms tumour and could be an important prognostic factor in Wilms tumours.