ArticleNature communications2025
Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers, 2 of them syntheses that pooled it.
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Who cites it
18 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk.Nature communications · 2026Pooled it
- Genetic drivers of etiologic heterogeneity in thyroid cancer.Nature communications · 2026Pooled it
- Large-Scale Analyses of GWAS Identify Five Key Pleiotropic Genes Involved in Complex Diseases.Genes · 2026Article
- Smoking exposure alters splicing of the nicotinic acetylcholine receptor subunit CHRNA5.Human genomics · 2026Article
- Regulatory Variation at TERT and TERC Shows Limited Association with Early-Onset Alzheimer's Disease in Carriers of the Mexican Founder MutationMedical sciences (Basel, Switzerland) · 2026Article
- Single-cell lung eQTL dataset of Asian never-smokers highlights the roles of alveolar cells in lung cancer etiology.bioRxiv : the preprint server for biology · 2026Article
- Relative leukocyte telomere length and the risk of lung cancer progression in individuals with pulmonary nodules.BMC medicine · 2026Article
- Integrative screening identifies functional variants and VNTRs underlying GWAS signals at the 5p15.33 multi-cancer susceptibility locus.medRxiv : the preprint server for health sciences · 2026Article
- TERT rs10069690 variant is linked to reduced cholangiocarcinoma incidence but adverse prognosis in patients undergoing resection.eGastroenterology · 2026Article
- Dyskerin dysfunction in cancer development: from telomere dysregulation to immune deficiency.American journal of cancer research · 2026Review
- Telomere Length Abnormality: Investigating Approaches and Correlations with Cancer, Bone Marrow Failure and Hematological Malignancies.Biomedicines · 2025Review
- Deciphering genetic susceptibility to clear cell renal cell carcinoma.Communications biology · 2025Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Article
- Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development.JHEP reports : innovation in hepatology · 2025Article
- Advanced MRI, Radiomics and Radiogenomics in Unravelling Incidental Glioma Grading and Genetic Status: Where Are We?Medicina (Kaunas, Lithuania) · 2025Review
- Gene therapy strategies for aging intervention.Cell insight · 2025Review
- Dysregulation of mRNA splicing in urothelial carcinoma: Clinical, diagnostic and therapeutic implications.Bladder cancer (Amsterdam, Netherlands)Review
Corrections and comments
- Erratum issued
- Update of
Authors and funding
23 authors.
Funding
Abstract
The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.
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