Telomere-related Genome Instability in Cancer

tumor types are in an astonishing state of disarray. The extent of genome scrambling was only appreciated after development of high-resolution techniques. Spectral karyotyping (M-FISH, SKY) has painted a picture of extensive reshuffling of chromosome segments. Techniques that display the differences between normal and cancer genomes, combined with DNA microarrays (array-CGH, Pinkel et al. 1998; ROMA, Lucito et al. 2003), have revealed countless copy number changes. What is the origin of this genome instability? Recent findings make a compelling case for the view that genome instability in human cancer is largely rooted in telomere dysfunction. Dysfunctional telomeres can explain most genome alterations observed in human cancer (Fig. 1). Moreover, the telomereshortening process that gives rise to dysfunctional telomeres takes place in the majority of human somatic cells, potentially explaining genome instability in many different human tumor types. Finally, a brief period of telomere dysfunction early in tumorigenesis can explain the transient nature of cancer genome instability. New data relating to these issues are discussed below.