Alternative Lengthening of Telomeres: Telomerase-Independent Immortality
About 10 to 15 percent of cancers keep their telomeres long without reactivating telomerase. This alternative lengthening of telomeres (ALT) uses homologous recombination to copy telomeric DNA between chromosome ends. It is strongly associated with loss of the chromatin regulators ATRX or DAXX and is most common in specific tumour types.
Quick Answer
About 10 to 15 percent of cancers keep their telomeres long without reactivating telomerase. This alternative lengthening of telomeres (ALT) uses homologous recombination to copy telomeric DNA between chromosome ends. It is strongly associated with loss of the chromatin regulators ATRX or DAXX and is most common in specific tumour types.
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DNA Repair and Genomic Instability
Open the complete 15-article guideA Recombination-Based Mechanism
In ALT-positive cells, telomeres act as templates for one another during recombination-mediated DNA synthesis, so telomere length is maintained or extended without telomerase. Hallmarks include very heterogeneous telomere lengths, extrachromosomal telomeric DNA circles, and ALT-associated nuclear bodies.
These features can be detected by specialised assays such as telomere fluorescence in situ hybridisation and C-circle assays, which are mostly research or reference-laboratory tools.
The ATRX and DAXX Connection
ATRX and DAXX form a complex that deposits the histone variant H3.3 at repetitive regions including telomeres. Loss of either protein destabilises telomeric chromatin and is found in the large majority of ALT-positive tumours, though loss alone is not sufficient to establish ALT.
Because ATRX or DAXX loss can be assessed by immunohistochemistry, it is often used as a surrogate marker in pathology.
Which Tumours Use It
ALT is enriched in pancreatic neuroendocrine tumours, many sarcomas including osteosarcoma and leiomyosarcoma, and paediatric glioblastoma and neuroblastoma. In pancreatic neuroendocrine tumours, ATRX or DAXX loss and ALT have been associated with more aggressive behaviour.
Telomerase-directed strategies would not be expected to affect ALT-positive tumours, which is one practical reason the distinction is studied.
Practical and Research Implications
The immediate practical use of an ALT assessment is prognostic in specific settings — notably pancreatic neuroendocrine tumours, where ATRX or DAXX loss and ALT mark more aggressive disease — and as a clue to an underlying ATRX-related tumour predisposition when the loss is germline.
Therapeutically, ALT is a research target rather than a treatment handle. ALT-positive cells rely heavily on the ATR kinase and on specific recombination and replication-stress pathways, and ATR inhibitors and related agents are being explored preclinically and in early trials for this group.
Key Takeaways
- ·ALT maintains telomeres by recombination rather than telomerase, in 10 to 15 percent of cancers.
- ·It is closely linked to ATRX or DAXX loss, which can be screened by immunohistochemistry.
- ·It is common in neuroendocrine tumours, sarcomas and some paediatric brain tumours.
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Frequently asked questions
How is ALT identified in a tumour?
By specialised assays such as telomere fluorescence in situ hybridisation and C-circle assays, often with ATRX or DAXX loss by immunohistochemistry used as a surrogate marker. These are mostly reference-laboratory tools.
Does ATRX or DAXX loss prove ALT is present?
No. Loss of either is found in most ALT-positive tumours but is not sufficient on its own to establish the ALT phenotype.
Why does the telomerase-versus-ALT distinction matter?
Telomerase-directed strategies would not be expected to affect ALT-positive tumours, and ALT is enriched in specific tumour types such as pancreatic neuroendocrine tumours, many sarcomas, and some paediatric brain tumours.
References
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