Figure 6. Two independent pathways trigger telomere dysfunction in cancer.

a | Telomere attrition induces telomere dysfunction and promotes gross chromosomal rearrangement due to breakage–fusion–bridge cycles (a non-reciprocal translocation is shown). Telomerase reactivation is a key event that stabilizes chromosome ends and supports the proliferation of tumours. b | Recurrent mutations in the TERT promoter are common in many cancers and seem to create a de novo binding site for the transcription factor GABP (GA-binding protein transcription factor). c | Deficiency in the shelterin subunit POT1 (protection of telomere 1) represent a novel mechanism that triggers telomere dysfunction in cancer. POT1 mutations induce telomere fragility and are associated with considerable telomere elongation. POT1 mutations also manifest in a mild chromosome fusion phenotype, which is predicted to induce chromosomal instability and augment tumour progression. d | POT1 mutations cluster primarily in its oligonucleotide-binding (OB) fold domains and are widespread across many tumour types.