TELOMERIC FUSIONS IN CULTURED HUMAN FIBROBLASTS AS A SOURCE OF GENOMIC INSTABILITY

In a human fibroblast clone we studied the evolution, during culture p ropagation, of a dicentric chromosome consisting of the end-to-end ass ociation of the short arm of chromosome 5 and the long arm of chromoso me 16, Dual-color fluorescence in situ hybridization (FISH) with paint ing probes allowed us to define the structure of a variety of derivati ve chromosomes and to identify the mechanisms by which they originated . Asymmetric interchanges involving the intercentromeric region of the dicentric, bridge-breakage-fusion events, or breaks followed by siste r chromatid fusion, originate unstable hetero- or homodicentric chromo somes with deletion or duplication; breakages not followed by reunion, or intradicentric recombination, presumably originate stable rearrang ed monocentric chromosomes. The variety of the derivatives is extremel y large because the observed events may involve any site of the interc entromeric region, although the majority of them occurs after a break in 16qh, The results of this investigation document the evolution thro ugh successive steps of a telomeric fusion, a chromosome anomaly frequ ently observed in tumor and senescent cells. They also demonstrate tha t in cultured cells of normal origin, starting with this anomaly, vari ous chromosomal mechanisms may produce translocations, duplications, a nd deletions. The karyotype instability produced by a telomeric fusion can be relevant for carcinogenesis because it may generate genetic ch anges critical in the multistep process of transformation. (C) Elsevie r Science Inc., 1997.