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Global and Gene-specific Epigenetic Patterns in Human Bladder Cancer Genomes Are Relatively Stable in Vivo and in Vitro over Time¹

Departments of Biochemistry and Molecular Biology [I. D. C. M., J. C., P. W. L., P. A. J.], Urology [G. L., P. A. J.], Pathology [D. S.], and Surgery [P. W. L.], Urologic Cancer Research Laboratory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089

We used a methylation-sensitive arbitrarily primed PCR technique to analyze, in a nonselective manner, methylation alterations at GC-rich regions of the genome in metachronous tumors and their derived cell lines from two patients with transitional cell carcinoma of the bladder. The methylation status of the majority of evaluable sequences (83%) remained unchanged in the tumors from both patients relative to a panel of normal urothelium samples obtained from individuals free of bladder disease, in which we measured <1% interindividual variation. The 17% of methylation alterations represents sequences altered in either a cancer-specific (3%), tumor-specific (1%), or patient-specific (13%) manner. The proportion of the altered sequences analyzed that were CpG islands corresponds to 7000 CpG islands altered in the genome. Surprisingly, few additional changes in methylation patterns were observed in cell lines derived from the tumors; however, all of the cell lines showed altered methylation in a common set of 3% of evaluable sequences. Three genes known to be aberrantly methylated in bladder cancer (p16, p15, and PAX6) were studied in detail by methylation-sensitive single nucleotide primer extension and showed increased methylation in culture at preexisting methylated sites for all of the exons but no de novo methylation in culture for the promoters in any cell line. Therefore, our investigation provides the first serial as well as parallel quantitation of the global epigenetic stability in two independent bladder cancer genomes over the course of progression and in culture. In addition, our investigation also provides the first direct comparison of the epigenetic and genetic patterns on the global scale, showing the epigenetic pattern to be relatively stable in vivo and in vitro over time within an individual.

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