Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse

Human carcinomas are intimately linked to advancing age. These cancers have complex cytogenetic profiles, including aneuploidy and chromosomal structu ral aberrations. While aged humans sustain a high rate of carcinomas,,nice bearing common tumor suppressor gene mutations typically develop soft tissu e sarcomas and lymphomas. One marked species distinction between human and mouse that bears on the predisposition to carcinogenesis lies in the radica l differences in length and regulation of the telomere, nucleoprotein compl exes that cap the ends of eukaryotic chromosomes. Recent cancer modeling st udies in the telomerase knockout p53 mutant mice revealed that telomere dyn amics might be relevant to carcinogenesis. In these mice there is a shift i n the tumor spectrum towards epithelial carcinomas, and these cancers emerg e with complex cytogenetic profiles classical for human carcinomas. In this m,iau, we suggest that the mechanism of fusion-bridge-breakage-translocati on triggered by critically short telomeres, may be one of the generators of genomic instability commonly seen in human carcinomas.