TERT Promoter Mutations: Switching Telomerase Back On
Most cells switch off telomerase after development, so telomeres shorten with each division until the cell stops dividing. Cancers must overcome this limit. In many tumour types they do so through two recurrent point mutations in the TERT gene promoter, which create new binding sites for transcription factors and switch telomerase expression back on.
Quick Answer
Most cells switch off telomerase after development, so telomeres shorten with each division until the cell stops dividing. Cancers must overcome this limit. In many tumour types they do so through two recurrent point mutations in the TERT gene promoter, which create new binding sites for transcription factors and switch telomerase expression back on.
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DNA Repair and Genomic Instability
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The two hotspot mutations, at positions commonly labelled C228T and C250T upstream of the TERT start site, each generate an identical 11-base-pair motif that is a binding site for ETS-family transcription factors. This increases TERT transcription and restores telomerase activity.
Because they lie outside the coding sequence, these mutations are missed by assays that only cover exons. Dedicated promoter coverage is needed to detect them.
Where They Occur
TERT promoter mutations are frequent in melanoma, glioblastoma, hepatocellular carcinoma, urothelial (bladder) cancer and some thyroid cancers. They are uncommon in many other tumour types, which instead maintain telomeres by other means.
In some settings they are among the earliest detectable changes; in others they appear later. Their prognostic weight is tumour-type specific and, in bladder cancer for example, high telomerase activity has correlated with outcome more consistently than promoter-mutation status alone.
Diagnostic Uses
In thyroid nodules and in central nervous system tumours, TERT promoter status contributes to molecular classification alongside other markers. In urine-based bladder cancer testing, promoter mutations are being studied as a detection and monitoring marker.
As with any single marker, the result is interpreted within a defined diagnostic algorithm rather than in isolation.
Therapeutic Interest and Current Limits
Reactivated telomerase is an appealing target because it is nearly universal in cancer and largely off in normal tissue, but direct telomerase inhibitors have not translated into broadly effective drugs, partly because the lag before critically short telomeres matter is long. TERT-promoter-mutant tumours are, for now, treated according to their histology and other drivers.
The mutations' firmest clinical value is diagnostic and prognostic: refining classification of thyroid nodules and central nervous system tumours, contributing to risk stratification in bladder cancer, and serving as a stable clonal marker for circulating-tumour-DNA and urine-based detection assays under study.
Key Takeaways
- ·Two recurrent TERT promoter point mutations create ETS binding sites and reactivate telomerase.
- ·They are common in melanoma, glioblastoma, liver, bladder and some thyroid cancers.
- ·They are non-coding and require assays that specifically cover the promoter region.
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Frequently asked questions
Will an exome or standard panel detect a TERT promoter mutation?
Not unless it specifically covers the promoter. The two hotspot changes lie outside the coding sequence, so assays that only sequence exons miss them.
Which cancers commonly carry TERT promoter mutations?
Melanoma, glioblastoma, hepatocellular carcinoma, urothelial (bladder) cancer and some thyroid cancers; they are uncommon in many other tumour types, which maintain telomeres by other means.
How do these mutations switch telomerase back on?
Each hotspot change creates an identical 11-base-pair motif that is a new binding site for ETS-family transcription factors, raising TERT transcription and restoring telomerase activity.
References
Continue Reading
Alternative Lengthening of Telomeres: Telomerase-Independent Immortality
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Clonal Evolution and Genomic Instability in Cancer
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MGMT Promoter Methylation: A Glioma Treatment Biomarker
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Mutational Signatures: Reading a Tumour's History
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APOBEC Mutagenesis: An Internal Source of Cancer Mutations
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Oncogene-Induced Senescence: A Built-In Barrier to Cancer
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