Fig. 7: Proposed model for functional effects of VNTR6-1 and rs10069690 contributing to multi-cancer associations within the 5p15.33 region.

a Cancer risk as a product of interactions between gene, replicative potential, and environment (G × R × E). TERT genetic variants VNTR6-1 and rs10069690 and environmental factors define the relative ratios of the isoforms encoding telomerase-functional TERT-FL and telomerase-nonfunctional TERT-β and INS1b isoforms. These isoforms affect cell proliferation, apoptosis, and telomere length, thus modulating cellular longevity and replicative potential, including homeostatic proliferation, which maintains tissue self-renewal, and regenerative proliferation, which responds to environmental factors and tissue damage. b The VNTR6-1-Long and rs10069690-T alleles, or their haplotype (Long-T), are associated with reduced cancer risk in tissues with low homeostatic but high regenerative potential (e.g., bladder). The anti-apoptotic effect of the TERT-β isoform reduces the need for regenerative proliferation, thus decreasing the risk of acquiring mutations from replicative errors. In tissues with no/low homeostatic and regenerative proliferation (e.g., brain, thyroid, ovary), the same alleles and Long-T haplotype are associated with elevated cancer risk. The anti-apoptotic effect of TERT-β contributes to extended cellular longevity, allowing the accumulation of more mutations from environmental exposures, such as reactive oxygen species (ROS), cellular metabolites, etc.