Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue.
Urothelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invasive tumors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is also characterized by a high rate of recurrence, and the presence of a field defect has been postulated. In this study, we compared the DNA methylation patterns between noninvasive and invasive UC and the DNA methylation patterns between normal-appearing urothelium from bladders with cancer and urothelium from cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 noninvasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urothelium from 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the noninvasive tumors and widespread hypermethylation in the invasive tumors, confirming that the two pathways differ epigenetically in addition to genetically. We also found that 12% of the loci were hypermethylated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field defect. X-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion but occurred independently across the urothelium of bladders with cancer. The hypomethylation present in noninvasive tumors may counterintuitively provide a biological explanation for the failure of these tumors to become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise.
Wolff
Erika M
EM
Department of Urology, USC Epigenome Center, and Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA.
Chihara
Yoshitomo
Y
Pan
Fei
F
Weisenberger
Daniel J
DJ
Siegmund
Kimberly D
KD
Sugano
Kokichi
K
Kawashima
Kiyotaka
K
Laird
Peter W
PW
Jones
Peter A
PA
Liang
Gangning
G
D041321:Chromosomes, Human, X / Q000235:genetics; D016000:Cluster Analysis; D015653:Cystectomy; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D044127:Epigenesis, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D014571:Urologic Neoplasms / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000473:pathology
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm