Telomere-related genome instability in cancer

Genome instability is a hallmark of most human cancers. Although a mutator phenotype is not required for tumorigenesis, it can foster mutations that promote tumor progression. Indeed, several inherited cancer-prone syndromes are due to mutations in DNA repair pathways. However, sporadic tumors are usually proficient in DNA repair, making it unlikely that unrepaired lesions are a major source of genome instability in sporadic cancers. A decade ago, I argued in another CSHL Press publication that a "collapse in telomere function can explain a significant portion of the genetic instability in tumors" (de Lange 1995). Since that time, the structure of mammalian telomeres has been analyzed, the consequences of telomere dysfunction have been determined, a mouse model for cancer-relevant aspects of telomere biology has been developed, and the nature and magnitude of cancer genome rearrangements have been revealed. In light of these developments, this is an opportune time to revisit the conjecture that telomere dysfunction contributes to genome instability in human cancer.