Alternative lengthening of telomeres: mechanism and the pathogenesis of cancer

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Abstract
Telomere maintenance and elongation allows cells to gain replicative immortality and evade cellular senescence during cancer development. While most cancers use telomerase to maintain telomere lengths, a subset of cancers engage the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is present in 5%–10% of all cancers, although the prevalence is dramatically higher in certain cancer types, including complex karyotype sarcomas, isocitrate dehydrogenase-mutant astrocytoma (WHO grade II–IV), pancreatic neuroendocrine tumours, neuroblastoma and chromophobe hepatocellular carcinomas. ALT is maintained through a homology-directed DNA repair mechanism. Resembling break-induced replication, this aberrant process results in dramatic cell-to-cell telomere length heterogeneity, widespread chromosomal instability and chronic replication stress. Additionally, ALT-positive cancers frequently harbour inactivating mutations in either chromatin remodelling proteins ( ATRX , DAXX and H3F3A ) or DNA damage repair factors ( SMARCAL1 and SLX4IP ). ALT can readily be detected in tissue by assessing the presence of unique molecular characteristics, such as large ultrabright nuclear telomeric foci or partially single-stranded telomeric DNA circles (C-circles). Importantly, ALT has been validated as a robust diagnostic and prognostic biomarker for certain cancer types and may even be exploited as a therapeutic target via small molecular inhibitors and/or synthetic lethality approaches.
Funding Information
  • Neuroendocrine Tumor Research Foundation
  • Boston University School of Medicine Department of Medicine (Evans Medical Foundation)
  • Congressionally Directed Medical Research Programs (HT9425-23-1-0671)
  • Congressionally Directed Medical Research Programs (HT9425-23-1-0819)
  • National Cancer Institute (R01CA201446)

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