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Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential

Author

Listed:
  • Oscar Florez-Vargas

    (National Cancer Institute)

  • Michelle Ho

    (National Cancer Institute)

  • Maxwell H. Hogshead

    (National Cancer Institute)

  • Brenen W. Papenberg

    (National Cancer Institute)

  • Chia-Han Lee

    (National Cancer Institute)

  • Kaitlin Forsythe

    (National Cancer Institute)

  • Kristine Jones

    (Frederick National Laboratory for Cancer Research)

  • Wen Luo

    (Frederick National Laboratory for Cancer Research)

  • Kedest Teshome

    (Frederick National Laboratory for Cancer Research)

  • Cornelis Blauwendraat

    (National Institute of Aging and National Institute of Neurological Disorders and Stroke)

  • Kimberly J. Billingsley

    (National Institute of Aging and National Institute of Neurological Disorders and Stroke)

  • Mikhail Kolmogorov

    (National Cancer Institute)

  • Melissa Meredith

    (UC Santa Cruz Genomics Institute)

  • Benedict Paten

    (UC Santa Cruz Genomics Institute)

  • Raj Chari

    (Frederick National Laboratory for Cancer Research)

  • Chi Zhang

    (Frederick National Laboratory for Cancer Research)

  • John S. Schneekloth

    (National Cancer Institute)

  • Mitchell J. Machiela

    (National Cancer Institute)

  • Stephen J. Chanock

    (National Cancer Institute)

  • Shahinaz M. Gadalla

    (National Cancer Institute)

  • Sharon A. Savage

    (National Cancer Institute)

  • Sam M. Mbulaiteye

    (National Cancer Institute)

  • Ludmila Prokunina-Olsson

    (National Cancer Institute)

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.

Suggested Citation

  • Oscar Florez-Vargas & Michelle Ho & Maxwell H. Hogshead & Brenen W. Papenberg & Chia-Han Lee & Kaitlin Forsythe & Kristine Jones & Wen Luo & Kedest Teshome & Cornelis Blauwendraat & Kimberly J. Billin, 2025. "Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56947-y
    DOI: 10.1038/s41467-025-56947-y
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