Begüm ÇALIM GÜRBÜZ, Başak BEKİROĞLU, Dilara YİTİZ, Şeyma AKER, Emre KORKMAZ, Halil Lütfi CANAT
İstanbul Medical Journal - 2026;27(3):233-237
Introduction: This study aims to evaluate the immunohistochemical expression of core circadian clock proteins, circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1), in patients with non-muscle-invasive urothelial carcinoma (NMIBC) and to determine their potential role in predicting disease progression. Methods: A total of 34 patients diagnosed with NMIBC who subsequently developed either progressive (n=20) or non-progressive (n=14) recurrence were included. Sixty-eight specimens from initial and recurrent biopsies, with a minimum 3-month interval, were analyzed. The expression of CLOCK and BMAL1 was quantified by independently assessing staining intensity and the percentage of positive cells, both of which were then used to calculate the H-score for each antibody. Statistical analyses were performed using SPSS 25.0, with significance set at p<0.05. Results: The mean age of 34 patients was 64.4+/-10.8 years. Significant stage migration was observed between initial and subsequent biopsies (p=0.01), with 9% of cases progressing to muscle-invasive disease. Progressive recurrence was significantly associated with initial pathological stage and grade (p=0.02), particularly in non-invasive papillary urothelial carcinoma (pTa) high-grade tumors (p=0.01). Peritumoral inflammatory infiltration was identified in 37% of cases and was significantly more frequent in high-grade stages (p=0.02) and invasive stages (p<0.01). Strong CLOCK expression was found in 99% of cases, while BMAL1 expression was significantly milder in pTa tumors (p=0.04). However, changes in CLOCK or BMAL1 H-scores (DeltaH-score) and shift work history were not significantly associated with time to disease progression (p>0.05). Conclusion: Our findings suggest that CLOCK protein activation occurs early and remains stable during the pathogenesis of urothelial carcinoma, while BMAL1 expression correlates with the pT stage. However, within this cohort, these circadian regulators did not serve as independent prognostic markers for disease progression. Further studies with larger sample sizes are needed to elucidate the complex role of the circadian system in tumor evolution.
