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<p>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 <i>TERT</i> 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 <i>TERT</i> 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 <i>TERT</i> expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of <i>TERT-</i>full-length (FL) to the alternative <i>TERT-β</i> isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from <i>TERT-FL</i> to <i>TERT-β</i> 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 <i>TERT</i> 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年2月16日

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  • Oscar Florez-Vargas,
  • Michelle Ho,
  • Maxwell H. Hogshead,
  • Brenen W. Papenberg,
  • Chia-Han Lee,
  • Kaitlin Forsythe,
  • Kristine Jones,
  • Wen Luo,
  • Kedest Teshome,
  • Cornelis Blauwendraat,
  • Kimberley J. Billingsley,
  • Mikhail Kolmogorov,
  • Melissa Meredith,
  • Benedict Paten,
  • Raj Chari,
  • Chi Zhang,
  • John S. Schneekloth,
  • Mitchell J. Machiela,
  • Stephen J. Chanock,
  • Shahinaz M. Gadalla,
  • Sharon A. Savage,
  • Sam M. Mbulaiteye,
  • Ludmila Prokunina-Olsson

摘要

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.