TERT Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients

Abstract

Telomerase reverse transcriptase gene promoter (TERTp) mutations are recognized as one of the most frequent genetic events in bladder cancer (BC). No studies have focused on the relevance of TERTp mutations in the specific group of tumors treated with Bacillus Calmette–Guérin (BCG) intravesical therapy. Methods — 125 non muscle invasive BC treated with BCG therapy (BCG-NMIBC) were screened for TERTp mutations, TERT rs2853669 single nucleotide polymorphism, and Fibroblast Growth Factor Receptor 3 (FGFR3) hotspot mutations. Results — TERTp mutations were found in 56.0% of BCG-NMIBC and were not associated with tumor stage or grade. FGFR3 mutations were found in 44.9% of the cases and were not associated with tumor stage or grade nor with TERTp mutations. The TERT rs2853669 single nucleotide polymorphism was associated with tumors of higher grade. The specific c.1-146G>A TERTp mutation was an independent predictor of nonrecurrence after BCG therapy (hazard ratio—0.382; 95% confidence interval—0.150–0.971, p = 0.048). Conclusions — TERTp mutations are frequent in BCG-NMIBC and -146G>A appears to be an independent predictive marker of response to BCG treatment with an impact in recurrence-free survival.

TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti‐CTLA4 treatment

“…TERT mutations are also outlined as markers of tumor aggressiveness and poor prognosis in several human cancer types 24‐28 . A recent study revealed that in bladder cancer, TERT promoter mutation appeared to be a potential predictive marker of response to Bacillus Calmette‐Guérin treatment which was regarded as one of the first and most successful oncological immunotherapy 29 . Therefore, TERT mutations may be used as a predictive marker for ICI responses.…”

TERTp mutations and p53 expression in head and neck cutaneous basal cell carcinomas with different aggressive features

“…TERTp mutation has not been reported as a prognostic factor in cBCCs [14][15][16] , at variance with other skin cancers, such as squamous cell carcinoma 41 and melanoma 18,33 in which TERTp mutations were associated with an ominous outcome. Contrarily, in the bladder cancer model, the − 146:G > A was an independent predictor of nonrecurrence after BCG therapy in the BCG-NMI tumors 42 .…”

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

“…Mutations in the core promoter region of TERT cause telomerase reactivation in 60-80% of urothelial bladder tumors 13 . The TERT C228T mutation has been shown to be significantly associated with the prognosis of bladder cancer, particularly with bladder recurrence in NMIBC 14 , whereas TERT C250 mutation appears to be an independent predictive marker of response to BCG treatment 15 . However, in our series, neither C228T nor C250 mutation was associated with prognosis of NMIBC or response to BCG-therapy.…”