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BackgroundTumor recurrence and progression in non-muscle invasive bladder cancer (NMIBC), therapy failure, and severe side effects in muscle invasive bladder cancer (MIBC) are the major challenges in the clinical management of bladder cancer (BC). Here, we identify new molecular targetable signatures to improve BC patients’ stratification and the outcome of current immunotherapies.Material and MethodsIn a prospective cohort of 70 BC patients, we assessed the genetic and molecular regulation of TERT in maintaining telomere length in parallel to immune checkpoint and microRNA expression.ResultsTERT was undetectable in healthy bladder tissues but upregulated in invasive BC stages and high tumor grade. Its expression was linked with the combined effect of the C250T mutation and THOR hypermethylation, associated with progressing tumors and maintaining of telomere length. In the same cohort, PD-L1 scored highest in NMIBC, while PD-L2 was upregulated in MIBC. We also show that miR-100-5p and 138-5p were highly expressed in healthy bladder specimens and cell line, while expression decreased in the BC tissues and BC cell lines. In line with the binding prediction for these miRNAs on target genes, miRs 100-5p and 138-5p expression strongly inverse correlated with TERT, PD-L1, and PD-L2 expression, but not PD1.ConclusionWe identify a loop involving TERT, PD1-ligands, and miR-138-5p in BC, that might represent not only a useful biomarker for improved diagnosis and patients’ stratification but also as a promising axis that might be therapeutically targeted in situ.

Highlights The diagnosis of primary malignant tumors is increasingly described with the improvement of life expectancy and the advent of new technologies. The management must be multidisciplinary and adapted to the condition of each patient. This entity affects elderly people with many comorbidities. Treatment should be the least aggressive and start with the most aggressive tumor. The elderly, a family history of neoplasia and smoking appear to be the factors favoring the appearance of multiple synchronous tumors. Our patient was an elderly person and a heavy smoker

Background: Human telomerase reverse transcriptase (hTERT) promoter mutations are common genetic events in bladder cancer (BC) and have been recognized as potential biomarkers for BC diagnosis and prognosis. Detection of TERT promoter mutations as urine-based tests has previously been reported to detect primary and recurrent BC. This study was planned to evaluate hTERT promoter mutations in both biopsies and urines from BC patients to assess the interest and the usefulness of introducing these biomarkers for better management of BC in Morocco. Methods: In a cohort study involving a series of BC 70 patients with different stages and grades, hTERT promoter mutations were identified in both fresh biopsies and urine sediments by PCR amplification and DNA sequencing. Results: Overall, hTERT promoter mutations were reported in 60% of cancer biopsies (42/70), the hotspot mutations C228T and C250T were respectively identified in 80.95% (34/42) and 16.67% (7/42) of positive cases. Other mutations: A161C and G149T were also reported and were obtained in 2.38% (1/42) and 2.38% (1/42), respectively. hTERT promoter mutations were identified in 30% of matched urine sediments (21/70) and showed an overall sensitivity of 50% and specificity of 100%. In patients with non-muscle invasive bladder cancer, no statistically significant association was detected between TERT promoter mutations and recurrence-free survival (HR: 1.224, 95% CI: 0.373-4.011, p = 0.739), and overall survival (HR: 0.363, 95% CI: 0.041-3.244, p = 0.364). Conclusion: hTERT promoter mutations are early events occurring with high frequencies and can be identified in the exfoliated cells, making them an interesting non-invasive biomarker for diagnosis and follow-up of bladder cancer.