Telomerase-independent paths to immortality in predictable cancer subtypes

Our plain-English summary of Telomerase-independent paths to immortality in predictable cancer subtypes, by S.T. Durant (Journal of Cancer, 2012).

The study

• Author: S.T. Durant
• Journal: Journal of Cancer
• Published: 2012;3:67-82
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The vast majority of cancers commandeer the activity of telomerase - the remarkable enzyme responsible for prolonging cellular lifespan by maintaining the length of telomeres at the ends of chromosomes. Telomerase is only normally active in embryonic and highly proliferative somatic cells. Thus, targeting telomerase is an attractive anti-cancer therapeutic rationale currently under investigation in various phases of clinical development. However, previous reports suggest that an average of 10-15% of all cancers lose the functional activity of telomerase and most of these turn to an Alternative Lengthening of Telomeres pathway (ALT). ALT-positive tumours will therefore not respond to anti-telomerase therapies and there is a real possibility that such drugs would be toxic to normal telomerase-utilising cells and ultimately select for resistant cells that activate an ALT mechanism. ALT exploits certain DNA damage response (DDR) components to counteract telomere shortening and rapid trimming. ALT has been reported in many cancer subtypes including sarcoma, gastric carcinoma, central nervous system malignancies, subtypes of kidney (Wilm's Tumour) and bladder carcinoma, mesothelioma, malignant melanoma and germ cell testicular cancers to name but a few. A recent heroic study that analysed ALT in over six thousand tumour samples supports this historical spread, although only reporting an approximate 4% prevalence. This review highlights the various methods of ALT detection, unravels several molecular ALT models thought to promote telomere maintenance and elongation, spotlights the DDR components known to facilitate these and explores why certain tissues are more likely to subvert DDR away from its usually protective functions, resulting in a predictive pattern of prevalence in specific cancer subsets.

In plain English

This article was a review, by a single author at AstraZeneca, of published laboratory and tumour research on Alternative Lengthening of Telomeres (ALT). ALT is a way some cancer cells keep dividing without the enzyme telomerase, which most cancers use to protect the ends of their chromosomes. The article did not study asbestos exposure. It described ways of detecting ALT, proposed models of how ALT works, and the DNA damage response proteins thought to be involved. Citing earlier studies, it reported that an estimated 85-90% of cancers use telomerase, and that a recent survey of over 6000 tissue samples found 3.7% to be ALT-positive. Mesothelioma was listed among the cancer types in which ALT has been reported, but the available text gave no mesothelioma figures. ALT was described as enriched in sarcomas. One cited study reported ALT in 38% (17/42) of gastric carcinoma cases. The author concluded that ALT components are extremely attractive treatment targets. The author also noted that ALT has not been screened in large enough groups within individual cancer types to estimate its frequency accurately.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on telomerase-independent telomere maintenance (ALT) in cell lines, yeast and human tumours
• Who was studied: No study population of its own. The review summarised published studies of cell lines, yeast and tumour samples, including a cited survey of over 6000 human tumour tissue samples.
• Exposure: No asbestos or other environmental or occupational exposure was studied. The subject was the biological mechanisms cancer cells use to maintain telomeres (telomerase versus ALT).
• Main results:
  • Citing earlier studies, the review reported that an estimated 85-90% of cancer tissue up-regulates telomerase activity.
  • In a cited survey of over 6000 tissue samples, 3.7% of tissues were determined to be ALT-positive. The author described this as lower than earlier estimates.
  • Mesothelioma was listed among the cancer types in which ALT has been reported. No mesothelioma-specific figures appear in the available text.
  • ALT was described as enriched in sarcomas, and also commonly found in certain central nervous system tumours, neuroendocrine tumours and testicular germ cell tumours.
  • One cited study found ALT in 38% (17/42) of gastric carcinoma tissues. The cited survey detected no ALT in 155 gastric adenocarcinoma samples.
  • Another cited study reported ALT in 32% of Wilms tumour samples (a childhood kidney cancer).
  • A cited study (Heaphy et al) found a 100% (19/19) correlation between ALT-positive status and ATRX or DAXX gene mutations in pancreatic neuroendocrine tumour samples.
• The authors' conclusion: The author concluded that ALT pathways and their components are extremely attractive targets for treating cancers that maintain telomeres without telomerase. The author added that redundancy and telomerase reactivation must be considered as possible challenges.
• Limitations the authors state:
  • ALT has not been screened in large enough groups within individual cancer types to give an accurate estimate of its frequency across diseases.
  • The role of recombination in ALT has only been studied in genetically modified yeast, mouse and human cell lines, so it is hard to judge how ALT is switched on in disease.
  • The roles of many DNA damage response components in normal telomere maintenance remain poorly understood.
  • The author stated that not all relevant studies could be included.

Topics

Medical terms in this study, explained in our Lexicon: Sarcoma, Carcinoma, Mesothelioma.

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