Methylation of the RUNX3 Promoter as a Potential Prognostic Marker for Bladder Tumor

Abstract

DNA methylation is a key regulator of gene transcription and genomic stability, and alterations in DNA methylation patterns are frequently detected in human tumors. Previously we reported that inactivation of RUNX3 by primarily epigenetic alterations in DNA methylation is closely associated with bladder tumor development, recurrence and progression. In the current series we evaluated the association between RUNX3 inactivation and bladder tumors after a long-term followup study. We used previously published data on the methylation patterns of RUNX3 in bladder tumor samples as well as 25 new data sets obtained by methylation specific polymerase chain reaction and direct DNA sequencing. Of the 149 patients examined 118 were followed periodically and included in the final analysis. Median followup was 49.8 months (range 1 to 146). RUNX3 promoter methylation was observed in 84 of the 118 tumor samples (71.2%) examined. RUNX3 methylation patterns correlated significantly with the development of invasive tumor, tumor progression, and overall and cancer specific survival (each p <0.05). Kaplan-Meyer curves showed identical results (p <0.05). Multivariate Cox regression models revealed that RUNX3 methylation status was a strong predictor of tumor progression and cancer specific survival. Results strongly suggest that inactivation of RUNX3 by the methylation of its promoter region is a significant risk factor for invasive bladder tumors, tumor progression and cancer specific survival. RUNX3 promoter methylation status could be a promising marker for assessing the prognosis of human bladder tumors.