Genome-wide DNA methylation profiles in both precancerous conditions and clear cell renal cell carcinomas are correlated with malignant potential and patient outcome

To clarify genome-wide DNA methylation profiles during multistage renal carcinogenesis, bacterial artificial chromosome array-based methylated CpG island amplification (BAMCA) was performed. Non-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas (RCCs) (N) was at the precancerous stage where DNA hypomethylation and DNA hypermethylation on multiple bacterial artificial chromosome (BAC) clones were observed. By unsupervised hierarchical clustering analysis based on BAMCA data for their N, 51 patients with clear cell RCCs were clustered into two subclasses, Clusters A_N(n=46) and B_N(n = 5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B_N, and the overall survival rate of patients in Cluster B_N was significantly lower than that of patients in Cluster A_N. By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters A_T (n = 43) and B_T(n = 8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster B_T, and the overall survival rate of patients in Cluster B_T was significantly lower than that of patients in Cluster A_T. Multivariate analysis revealed that belonging to Cluster B_T was an independent predictor of recurrence. Cluster B_N was completely included in Cluster B_T, and the majority of the BAC clones that significantly discriminated Cluster B_N from Cluster A_N also discriminated Cluster B_T from Cluster A_T. In individual patients, DNA methylation status in N was basically inherited by the corresponding clear cell RCC. DNA methylation alterations in the precancerous stage may generate more malignant clear cell RCCs and determine patient outcome.