Cancer esearch or and Stem Cell Biology que DNA Methylation Patterns Distinguish Noninvasive Invasive Urothelial Cancers and Establish an R enetic Field Defect in Premalignant Tissue

nloaded thelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invamors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is haracterized by a high rate of recurrence, and the presence of a field defect has been postulated. In tudy, we compared the DNA methylation patterns between noninvasive and invasive UC and the methylation patterns between normal-appearing urothelium from bladders with cancer and urotherom cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 vasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urotherom 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the nonve tumors and widespread hypermethylation in the invasive tumors, confirming that the two ays differ epigenetically in addition to genetically. We also found that 12% of the loci were hyperlated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field de-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion curred independently across the urothelium of bladders with cancer. The hypomethylation present invasive tumors may counterintuitively provide a biological explanation for the failure of these tuto become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might mors contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise. Cancer Res; 70(20); 8169–78. ©2010 AACR.