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

• Published in: Nature communications Vol. 16; no. 1; pp. 1676 - 20
• Main Authors: Florez-Vargas, Oscar, Ho, Michelle, Hogshead, Maxwell H., Papenberg, Brenen W., Lee, Chia-Han, Forsythe, Kaitlin, Jones, Kristine, Luo, Wen, Teshome, Kedest, Blauwendraat, Cornelis, Billingsley, Kimberley J., Kolmogorov, Mikhail, Meredith, Melissa, Paten, Benedict, Chari, Raj, Zhang, Chi, Schneekloth, John S., Machiela, Mitchell J., Chanock, Stephen J., Gadalla, Shahinaz M., Savage, Sharon A., Mbulaiteye, Sam M., Prokunina-Olsson, Ludmila
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/2; 13/31; 14/19; 38/88; 42/35; 42/44; 45/23; 45/41; 45/43; 45/91; 631/208/200; 631/208/205; 631/208/68; Age; Alleles; Alternative splicing; Alternative Splicing - genetics; Apoptosis; Apoptosis - genetics; Bioinformatics; Cancer; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Chromosome 5; Clonal deletion; CRISPR; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Haplotypes; Health risks; Humanities and Social Sciences; Humans; Introns - genetics; Loci; Longevity; Minisatellite Repeats - genetics; multidisciplinary; Neoplasms - genetics; Neoplasms - pathology; Polymorphism, Single Nucleotide; Risk; RNA-directed DNA polymerase; Science; Science (multidisciplinary); Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomerase reverse transcriptase; Telomeres
• DOI: 10.1038/s41467-025-56947-y
• ISSN: 2041-1723

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. Several multi-cancer GWAS loci within the region encoding telomerase reverse transcriptase (TERT) have been identified. Here, the authors explore the locus within TERT intron 4, link it with a variable number tandem repeat (VNTR), and investigate its biological significance and role in cancer.