Telomeres are comprised of a repetitive hexanucleotide DNA sequence (TTAGGG) that are bound by the six-member shelterin complex. Telomeres maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing the chromosome ends from being recognized as double-strand breaks, thereby averting chromosomal fusions. In normal somatic cells, critical telomere shortening leads to p53-dependent senescence or apoptosis. In cancer cells, cell cycle checkpoints are typically abrogated. Critical telomere shortening is a common abnormality observed early in tumorigenesis, where it likely helps drive malignant transformation and tumor progression via telomere destabilization and concomitant chromosomal instability. Given that dysfunctional telomeres contribute to genomic instability and promotes tumorigenesis, we and others, have hypothesized that increased telomere shortening in cancer cells would drive the evolution of cell clones capable of invasion, extravasation, and metastasis.

Approximately 10% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype is identified at the cellular level by the presence of ALT-associated promyelocytic leukemia protein nuclear bodies (APBs). The APBs contain large amounts of telomeric DNA, in addition to PML protein and other proteins involved in telomere binding, DNA replication, and recombination. Hallmarks of ALT-positive cells include striking telomere length heterogeneity and alterations in the chromatin remodeling proteins ATRX or DAXX. Other characteristics include extensive chromosomal instability, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break repair.