Telomere stability pathway genes as predictors of susceptibility and prognosis in urothelial bladder cancer: review and bioinformatics analyses.

Telomeres play a crucial role in carcinogenesis, particularly environmentally related cancers such as urothelial bladder cancer (UBC). Evidence indicates that exposure to environmental pollutants might accelerate telomere erosion and further induce premature senescence, increasing morbidity and mortality rates of cancer. In addition to environmental exposure, variants in telomere-related genes may influence relative telomere length (RTL). This systematic review discusses the pathophysiological aspects of UBC, the mechanisms regulating telomere homeostasis, and factors contributing to telomere dysfunction, with a focus on genetic variations. The available literature on genetic variants and their impact on UBC susceptibility, prognosis, and RTL was summarized and discussed. A total of 17 eligible studies examining 63 polymorphisms across 11 telomere-related genes/loci were included, with telomerase reverse transcriptase (TERT) being the most investigated gene. Most studies focused on disease susceptibility, whereas fewer explored prognostic implications or associations with RTL. Further, bioinformatics analyses were conducted to explore mutation and expression patterns of these genes in UBC. Data from The Cancer Genome Atlas (TCGA) demonstrated that tumors with mutations in genes related to RTL exhibit a higher tumor mutation burden than those without such mutations, and that TEP1 and POT1 are the most frequently mutated genes in UBC. These findings reinforce the role of telomere instability as a key mechanism in bladder carcinogenesis. This review suggests that variants in genes encoding telomerase and telomere-related proteins play a critical role in UBC susceptibility and prognosis, and that personalized treatment targeting telomere disruption may be expanded to bring clinical benefits for UBC patients.