Telomere-related Genome Instability in Cancer

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Abstract
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 tomutations in DNA repair pathways. However, sporadic tumors are usually proficient in DNA repair, making it unlikely thatunrepaired lesions are a major source of genome instability in sporadic cancers. A decade ago, I argued in another CSHLPress 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 telomeredysfunction have been determined, a mouse model for cancer-relevant aspects of telomere biology has been developed, andthe nature and magnitude of cancer genome rearrangements have been revealed. In light of these developments, this is an opportunetime to revisit the conjecture that telomere dysfunction contributes to genome instability in human cancer.