Purpose: DNA methylation is a key regulator of gene transcription and genomic stability, and alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. We elucidated the significance of aberrant protein expression of DNA methyltransferase (DNMT) 1, a major enzyme involved in the determination of genomic methylation patterns, during human urothelial carcinogenesis. Materials and Methods: A total of 61 samples of normal urothelium, 89 noncancerous urothelium samples showing no remarkable histological changes from patients with bladder cancer (NBCs), 78 dysplastic urothelium samples and 174 transitional cell carcinoma samples (TCCs) were subjected to immunohistochemical analysis for DNMT1. Results: The incidence of nuclear DNMT1 immunoreactivity in NBCs (65%) was significantly higher than in normal urothelium (20%, p <0.0001) and the incidence was even higher in dysplastic urothelium samples (84%, p = 0.0017). The incidence of nuclear DNMT1 immunoreactivity was 87% in TCCs and the intensity of nuclear immunoreactivity was markedly increased in TCCs compared with that in dysplastic urothelium samples. DNMT1 expression levels had already increased in NBCs in which the proliferating cell nuclear antigen labeling index had not yet increased. Increased DNMT1 protein expression correlated significantly with histological grade (p <0.0001). DNMT1 protein expression was higher in nonpapillary tumors (p = 0.0001), especially flat carcinoma in situ, than in papillary tumors. Conclusions: Progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but rather it is associated with urothelial carcinogenesis even during the precancerous stages. In particular, it is associated with the development of flat carcinoma in situ, which is considered to be a precursor of nodular invasive carcinoma of the bladder.
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