title: Phosphorylated H2AX in noninvasive low grade urothelial carcinoma of the bladder: correlation with tumor recurrence.
abstract: OBJECTIVE
  Histone modifications have been linked to DNA replication, transcription and repair. The phosphorylation of histone H2AX at serine 139 (gamma-H2AX) is associated with DNA breaks. gamma-H2AX has been shown to be expressed in bladder urothelial carcinoma. To our knowledge studies of the relationship of gamma-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.
  
  
  METHODS
  Immunohistochemical expression of gamma-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 gamma-H2AX negative than in gamma-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 gamma-H2AX staining. However, the difference in progression between gamma-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 gamma-H2AX expression for predicting outcome in low grade urothelial carcinoma cases.
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Wang L
authors.initials: WL
authors.lastname: Cheung
authors.forename: Roula
authors.initials: R
authors.lastname: Albadine
authors.forename: Theresa
authors.initials: T
authors.lastname: Chan
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D010766:Phosphorylation; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; D006657:Histones