Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential
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.
Authors
- Sharon A. Savage (ORCID: https://orcid.org/0000-0001-6006-0740)
- Ludmila Prokunina‐Olsson (ORCID: https://orcid.org/0000-0002-9622-2091)
- Melissa Meredith (ORCID: https://orcid.org/0000-0001-5736-3193)
- Maxwell H. Hogshead (ORCID: https://orcid.org/0000-0002-4976-8067)
- Mikhail Kolmogorov (ORCID: https://orcid.org/0000-0002-5489-9045)
- Kimberly J Billingsley (ORCID: https://orcid.org/0000-0002-6554-0476)
- Kristine M. Jones (ORCID: https://orcid.org/0000-0003-1584-8920)
- Oscar Flórez-Vargas (ORCID: https://orcid.org/0000-0002-4393-2612)
- Raj Chari (ORCID: https://orcid.org/0000-0002-2216-313X)
- John S. Schneekloth (ORCID: https://orcid.org/0000-0001-7459-783X)
- Benedict Paten (ORCID: https://orcid.org/0000-0001-8863-3539)
- Wen Luo
- Sam M. Mbulaiteye (ORCID: https://orcid.org/0000-0002-8273-9831)
- Shahinaz M. Gadalla (ORCID: https://orcid.org/0000-0002-3255-8143)
- Kedest Teshome
- Mitchell J. Machiela (ORCID: https://orcid.org/0000-0001-6538-9705)
- Cornelis Blauwendraat (ORCID: https://orcid.org/0000-0001-9358-8111)
- Brenen W. Papenberg (ORCID: https://orcid.org/0000-0003-3734-3018)
- Chia‐Han Lee (ORCID: https://orcid.org/0000-0002-6013-9659)
- Stephen J. Chanock (ORCID: https://orcid.org/0000-0002-2324-3393)
- Chi Zhang (ORCID: https://orcid.org/0009-0000-4820-5126)
- Michelle Ho (ORCID: https://orcid.org/0000-0002-9143-2241)
- Kaitlin Forsythe (ORCID: https://orcid.org/0000-0002-1075-0935)
Institutions
- Leidos (United States) (US)
- University of California, Santa Cruz (US)
- National Institute of Neurological Disorders and Stroke (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-16
- DOI
- https://doi.org/10.1038/s41467-025-56947-y
- Citations
- 10
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 11.64
Funders
- Wellcome Trust
- British Heart Foundation
- Diabetes UK
- National Institutes of Health
- Health Resources and Services Administration
- Medical Research Council
- National Heart, Lung, and Blood Institute
- Office of Naval Research
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- Division of Cancer Epidemiology and Genetics, National Cancer Institute