Prognostic Significance of Methylation Profiles in Urothelial Carcinomas of the Bladder
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Background : Study on epigenetics of urothelial carcinomas has expanded and allowed better understanding of their correlation with clinicopathologic features. The aim of this study was to determine reliable predictive epigenetic markers for patients with urothelial carcinoma of urinary bladder. Methods : In 64 urothelial carcinomas of the urinary bladder, methylationspecific polymerase chain reaction with RAS association domain family 1A (RASSF1A), adenomatous polyposis coli (APC), death-associated protein-kinase (DAPK), runt-related transcription factor 3 (RUNX3), p14, p16 and MGMT was performed and correlated the results with p53 mutations, DNA ploidy, clinicopathologic parameters and recurrences. Results : Hypermethyation of RASSF1A, APC, DAPK, RUNX3, p14, p16 and MGMT promoters was observed in 35 (54.7%), 29 (45.3%), 18 (28.1%), 18 (28.1%), 9 (14.1%), 2 (3.1%), and 6 (9.4%) cases, respectively. Hypermethylation of RUNX3 and APC was significantly associated with high histologic grades and aneuploidy. Methylation of DAPK was significantly associated with muscle invasion. Methylation of DAPK and RUNX3 genes was significantly associated with recurrence. In survival analyses, methylation of RUNX3 gene and methylation-high (methylation at two or more loci) phenotype was significantly associated with poor recurrence-free survival. Conclusions : Methylation of RUNX3 gene and methylation-high phenotype are significant indicator of recurrence.
Abstract
Background : Study on epigenetics of urothelial carcinomas has expanded and allowed better understanding of their correlation with clinicopathologic features. The aim of this study was to determine reliable predictive epigenetic markers for patients with urothelial carcinoma of urinary bladder. Methods : In 64 urothelial carcinomas of the urinary bladder, methylationspecific polymerase chain reaction with RAS association domain family 1A (RASSF1A), adenomatous polyposis coli (APC), death-associated protein-kinase (DAPK), runt-related transcription factor 3 (RUNX3), p14, p16 and MGMT was performed and correlated the results with p53 mutations, DNA ploidy, clinicopathologic parameters and recurrences. Results : Hypermethyation of RASSF1A, APC, DAPK, RUNX3, p14, p16 and MGMT promoters was observed in 35 (54.7%), 29 (45.3%), 18 (28.1%), 18 (28.1%), 9 (14.1%), 2 (3.1%), and 6 (9.4%) cases, respectively. Hypermethylation of RUNX3 and APC was significantly associated with high histologic grades and aneuploidy. Methylation of DAPK was significantly associated with muscle invasion. Methylation of DAPK and RUNX3 genes was significantly associated with recurrence. In survival analyses, methylation of RUNX3 gene and methylation-high (methylation at two or more loci) phenotype was significantly associated with poor recurrence-free survival. Conclusions : Methylation of RUNX3 gene and methylation-high phenotype are significant indicator of recurrence.
참고문헌 (30)
- Greenlee RT, "Cancer statistics,2000", CA Cancer J Clin, 50, pp.7~33 (2000)
- Holma_ng S, "Recurrence and progression in low grade papillary urothelial tumors", J Urol, 162(3 Pt 1), pp.702~707 (1999)
- Negraes PD, "DNA methylation patterns in bladder cancer and washing cell sediments:a perspective for tumor recurrence detection", BMC Cancer, 8, pp.238~ (2008)
- Jones PA, "The fundamental role of epigenetic events in cancer", Nat Rev Genet, 3, pp.415~428 (2002)
- Kim WJ, "RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors", Cancer Res, 65, pp.9347~9354 (2005)
- Maruyama R, "Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features", Cancer Res, 61, pp.8659~8663 (2001)
- Muto S, "Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer", Cancer Res, 60, pp.4021~4025 (2000)
- Kim EJ, "Methylation of the RUNX3 promoter as a potential prognostic marker for bladder tumor", J Urol, 180, pp.1141~1145 (2008)
- Dulaimi E, "Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel", Clin Cancer Res, 10, pp.1887~1893 (2004)
- Kim YK, "Epigenetic markers as promising prognosticators for bladder cancer", Int J Urol, 16, pp.17~22 (2009)
- Yates DR, "Promoter hypermethylation identifies progression risk in bladder cancer", Clin Cancer Res, 13, pp.2046~2053 (2007)
- Nakagawa T, "DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis", J Urol, 173, pp.1767~1771 (2005)
- Chan MW, "Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients", Clin Cancer Res, 8, pp.464~470 (2002)
- Catto JW, "Promoter hypermethylation is associated with tumor location,stage,and subsequent progression in transitional cell carcinoma", J Clin Oncol, 23, pp.2903~2910 (2005)
- Tada Y, "The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers", Cancer Res, 62, pp.4048~4053 (2002)
- Pu RT, "Methylation profiling of urothelial carcinoma in bladder biopsy and urine", Acta Cytol, 50, pp.499~506 (2006)
- Ellinger J, "Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer", J Urol, 179, pp.346~352 (2008)
- Lin HH, "Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine", Urol Oncol, 28, pp.597~602 (2010)
- Amaral JD, "The role of p53 in apoptosis", Discov Med, 9, pp.145~152 (2010)
- Robles AI, "The p53 network in lung carcinogenesis", Oncogene, 21, pp.6898~6907 (2002)
- Sarkis AS, "Nuclear overexpression of p53 protein in transitional cell bladder carcinoma:a marker for disease progression", J Natl Cancer Inst, 85, pp.53~59 (1993)
- Jarmalaite S, "Promoter hypermethylation in tumour suppressor genes shows association with stage,grade and invasiveness of bladder cancer", Oncology, 75, pp.145~151 (2008)
- Brait M, "Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer", Cancer Epidemiol Biomarkers Prev, 17, pp.2786~2794 (2008)
- Edge SB, "AJCC cancer staging manual. 7th ed" (2010), Springer
- Koss LG, "Flow cytometric measurements of DNA and other cell components in human tumors:a critical appraisal", Hum Pathol, 20, pp.528~548 (1989)
- McLemore DD, "Modified methodology to improve flow cytometric DNA histograms from paraffin-embedded material", Stain Technol, 65, pp.279~291 (1990)
- Wolff EM, "RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking", Cancer Res, 68, pp.6208~6214 (2008)
- Chi XZ, "Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination", Cancer Res, 69, pp.8111~8119 (2009)
- Cameron EE, "Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer", Nat Genet, 21, pp.103~107 (1999)
- Momparler RL, "Cancer epigenetics", Oncogene, 22, pp.6479~6483 (2003)