Telomere dysfunction triggers extensive DNA fragmentation and evolution ofcomplex chromosome abnormalities in human malignant tumors

Although mechanisms for chromosomal instability in tumors have been describ ed in animal and in vitro models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoi nt profiles were constructed for 102 pancreatic carcinomas and 140 osteosar comas, two tumor types characterized by extensive genomic instability. Case s with few chromosomal alterations showed a preferential clustering of brea kpoints to the terminal bands, whereas tumors with many changes showed prim arily interstitial and centromeric breakpoints. The terminal breakpoint fre quency was negatively correlated to telomeric TTAGGG repeat length, and flu orescence in situ hybridization with telomeric TTAGGG probes consistently i ndicated shortened telomeres and > 10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable r ing and dicentric chromosomes, mitotic figures were also evaluated. Anaphas e bridges were found in all cases, and fluorescence in situ hybridization d emonstrated extensive structural rearrangements of chromosomes, with termin al transferase detection showing fragmented DNA in 5-20% o Interphase cells . Less than 2% of cells showed evidence of necrosis or apoptosis, and telom erase was expressed in the majority o cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage event s in pancreatic carcinomas and osteosarcomas, leading to a continuous reorg anization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for pre venting complete genomic deterioration and maintaining cellular survival.