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.