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Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer

¹ Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine; ² Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; ³ Ludwig Institute for Cancer Research/Fundação Antonio Prudente, São Paulo, São Paulo, Brazil; ⁴ Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁵ Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Mohammad Obaidul Hoque, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II, 5M, Baltimore, MD 21231. Phone: 410-502-8778; Fax: 410-614-1411. E-mail: mhoque1{at}jhmi.edu

Purpose: The aims of our study were to elucidate the role of methylation of a large panel of genes during multistage pathogenesis of bladder cancer and to correlate our findings with patient age and other clinicopathologic features.

Experimental Design: We studied the methylation status of 21 genes by quantitative methylation-specific PCR in an evaluation set of 25 tumor and 5 normal samples. Based on methylation frequency in tumors and normals in gene evaluation set, we selected 7 candidate genes and tested an independent set of 93 tumors and 26 normals. The presence or absence of methylation was evaluated for an association with cancer using cross-tabulations and ² or Fisher's exact tests as appropriate. All statistical tests were two-sided.

Results: Most primary tumors (89 of 93, 96%) had methylation of one or more genes of independent set; 53 (57%) CCNA1, 29 (31%) MINT1, 36 (39%) CRBP, 53 (57%) CCND2, 66 (71%) PGP9.5, 60 (65%) CALCA, and 78 (84%) AIM1. Normal uroepithelium samples from 26 controls revealed no methylation of the CCNA1 and MINT1 genes, whereas methylation of CRBP, CCND2, PGP9.5, and CALCA was detected at low levels. All the 7 genes in independent set were tightly correlated with each other and 3 of these genes showed increased methylation frequencies in bladder cancer with increasing age. PGP9.5 and AIM1 methylation correlated with primary tumor invasion.

Conclusion: Our results indicate that the methylation profile of novel genes in bladder cancers correlates with clinicopathologic features of poor prognosis and is an age-related phenomenon. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2786–94)