Phosphorylated H2AX in Noninvasive Low Grade Urothelial Carcinoma of the Bladder: Correlation With Tumor Recurrence

Wang L. Cheung, Roula Albadine, Theresa Chan, R. Sharma, George J. Netto

Research output: Contribution to journalArticle

Abstract

Purpose: Histone modifications have been linked to DNA replication, transcription and repair. The phosphorylation of histone H2AX at serine 139 (γ-H2AX) is associated with DNA breaks. γ-H2AX has been shown to be expressed in bladder urothelial carcinoma. To our knowledge studies of the relationship of γ-H2AX expression and the clinical outcome of urothelial carcinoma are lacking. Hence, we evaluated the rate of H2AX phosphorylation in low grade bladder urothelial carcinoma and assessed its potential role for predicting recurrence and/or progression. Materials and Methods: Immunohistochemical expression of γ-H2AX using a polyclonal antibody was retrospectively assessed in 2 groups of patients from The Johns Hopkins Hospital with low grade bladder urothelial carcinoma. Group 1 consisted of transurethral resection biopsies from 18 patients from 2004 to 2006 that were retrieved from our surgical pathology files. Group 2 consisted of 42 archival transurethral biopsies obtained between 1971 and 1995 with longer followup that were used to construct a tissue microarray. Results: On univariate analysis recurrence in the entire cohort was more likely to develop in γ-H2AX negative than in γ-H2AX positive cases (24 of 32 or 81% vs 13 of 28 or 46%). The difference in recurrence was statistically significant (p = 0.02). The same was true in group 2 (16 of 21 cases or 76% vs 9 of 21 or 43%, p = 0.02). Female gender and intravesical therapy were also associated with a higher recurrence rate in our cohort. A higher progression rate was noted in group 2 patients and in the entire cohort in association with negative γ-H2AX staining. However, the difference in progression between γ-H2AX negative and positive tumors was not statistically significant. On multivariate analysis only patient gender and prior intravesical treatment remained predictive of recurrence (p <0.03). Conclusions: Our data suggest that epigenetic alterations may have an important role in the mechanism of bladder tumor recurrence. Analysis in a larger cohort is needed to further assess our current preliminary findings of the role of γ-H2AX expression for predicting outcome in low grade urothelial carcinoma cases.

Original languageEnglish (US)
Pages (from-to)1387-1392
Number of pages6
JournalJournal of Urology
Volume181
Issue number3
DOIs
StatePublished - Mar 1 2009

Keywords

  • epigenesis
  • genetic
  • histones
  • urinary bladder
  • urinary bladder neoplasms
  • urothelium

ASJC Scopus subject areas

  • Urology

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