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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 AN(n= 46) and BN(n = 5). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BN, and the overall survival rate of patients in Cluster BNwas significantly lower than that of patients in Cluster AN. By unsupervised hierarchical clustering analysis based on BAMCA data for their RCCs, 51 patients were clustered into two subclasses, Clusters AT(n = 43) and BT(n = 8). Clinicopathologically aggressive clear cell RCCs were accumulated in Cluster BT, and the overall survival rate of patients in Cluster BTwas significantly lower than that of patients in Cluster AT. Multivariate analysis revealed that belonging to Cluster BTwas an independent predictor of recurrence. Cluster BNwas completely included in Cluster BT, and the majority of the BAC clones that significantly discriminated Cluster BNfrom Cluster ANalso discriminated Cluster BTfrom Cluster AT. 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.

carcinogenesis

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