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.
- neuroendocrine cells
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Handling editor Vikram Deshpande.
Contributors JOM, JK, RLF and CMH contributed to the drafting of the manuscript and review and approval of the final version.
Funding This work is supported by the US Department of Defense Rare Cancer Research Program grants HT9425-23-1-0819 and HT9425-23-1-0671 (CMH), the National Cancer Institute grant R01CA201446 (RLF), the Neuroendocrine Tumor Research Foundation (CMH) and the Evans Medical Foundation at Boston University, School of Medicine Department of Medicine (CMH).
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.