To clarify genome-wide DNA methylation profiles during multistage urothelial carcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification (BAMCA) was performed in 18 normal urothelia obtained from patients without urothelial carcinomas (UCs) (C), 17 noncancerous urothelia obtained from patients with UCs (N), and 40 UCs. DNA hypo- and hypermethylation on multiple BAC clones was observed even in N compared to C. Principal component analysis revealed progressive DNA methylation alterations from C to N, and to UCs. DNA methylation profiles in N obtained from patients with invasive UCs were inherited by the invasive UCs themselves, that is DNA methylation alterations in N were correlated with the development of more malignant UCs. The combination of DNA methylation status on 83 BAC clones selected by Wilcoxon test was able to completely discriminate N from C, and diagnose N as having a high risk of carcinogenesis, with 100% sensitivity and specificity. The combination of DNA methylation status on 20 BAC clones selected by Wilcoxon test was able to completely discriminate patients who suffered from recurrence after surgery from patients who did not. The combination of DNA methylation status for 11 BAC clones selected by Wilcoxon test was able to completely discriminate patients with UCs of the renal pelvis or ureter who suffered from intravesical metachronous UC development from patients who did not. Genome-wide alterations of DNA methylation may participate in urothelial carcinogenesis from the precancerous stage to UC, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication.
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