Methylation status of RASSF1A gene promoter in upper tract urothelial carcinoma and its clinical significance

OBJECTIVE: To investigate the methylation status of the RASSF1A gene promoter in upper tract urothelial carcinoma (UTUC) tissues and its correlation with clinicopathologic characteristics and postoperative recurrence of primary UTUC. METHODS: In a retrospective design, a total of 687 patients who underwent surgeries for primary UTUC in the urology department of Peking University First Hospital were enrolled. The methylation status of the RASSF1A gene promoter was analyzed using methylation-sensitive polymerase chain reaction on tumor specimens. RESULTS: Aberrant methylation for the RASSF1A gene promoter was detected in 183 (26.6%) DNA samples in total. Aberrant methylation of the RASSF1A gene was strongly associated with tobacco consumption (P=0.044), ipsilateral hydronephrosis (P<0.001 ), tumor location (P<0.001 ), tumor stage (P=0.001), tumor grade (P=0.007), lymph node metastasis (P=0.001) and growth pattern (P=0.013). The methylated RASSF1A gene promoter was an independent risk factor for bladder recurrence (P<0.001, HR=0.471) and contralateral recurrence (P=0.030, HR=0.269) of UTUC after surgery. Hypermethylated RASSF1A was predictive for improved bladder recurrence-free survival (BRFS) (P<0.001) and contralateral recurrence-free survival (CRFS) (P=0.021) in the UTUC patients. Compared with the patients with unmethylated RASSF1A, the patients containing tumors with hypermethylated RASSF1A had tendency toward longer recurrence-free survival time [(114.4±3.9) months vs. (84.0±3.2) months for BRFS, (138.1±1.8) months vs. (132.9±1.9) months for CRFS] and higher estimated cumulative recurrence-free survive rates ( five-year survival rate for example, 79.8%±3.4% vs. 57.4%±2.6% for BRFS, 98.9%±0.8% vs. 93.0%±1.4% for CRFS). Additionally, tumor multifocality (P=0.002, HR=1.538), and ureteroscopy before surgery (P=0.001, HR=1.725) were independent risk factors for bladder recurrence in postoperative UTUC patients. CONCLUSION: The methylation status of the RASSF1A gene promoter appears to be a promising epigenomic biomarker for assessing the aggressiveness of UTUC and a predictor predicting the urinary tract recurrence after surgery.