Ki-67 and Cell Cycle Regulators p53, p63 and cyclinD1 as Prognostic Markers for Recurrence/ Progression of Bladder Urothelial Carcinoma

Abstract

Deregulation of the cell cycle regulating genes is common in urothelial bladder carcinoma (UBC). We aimed to examine the prognostic significance of ki-67, p53, p63 and cyclinD1expression in UBC and to identify optimal cut-off points to help identifying patients at high risk of tumor recurrence. We evaluated the immunohistochemical expression of ki-67, p53, p63 and cyclinD1 in 100 UBCs. The conventional and the classification and regression trees-guided (CART-guided) methods were utilized to determine the independent predictors of tumor recurrence. The p53 and Ki-67 expression didn't associate significantly with tumor recurrence.p63 and cyclinD1 exhibited significant hazard ratios. Using CART, no recurrence was observed when p63 was ≥87.5%. The recurrence incidence increased and the disease free survival (DFS) time shortened as the p63 decreased. CyclinD1 associated significantly with tumor recurrence only if p63 was <35%. Using the CART cut-off values¬, cases were categorized into three groups; (groups I: p63 ≥ 35%, II: p63 < 35% and cyclinD1 < 10% and III: p63 < 35% and cyclinD1 ≥ 10%). Group I patients revealed the least incidence of recurrence at the longest DFS. Group III had the worst prognosis followed by Group II. p63 represents a surrogant biomarker to predict UBC recurrence.CyclinD1 can be used only when p63 is <35%. CART proved helpful with data among which the number of cases with positive outcomes is too small relative to the number of studied predictors. Large cohort studies for ki-67 and p53 are recommended to be performed with standardized criteria as regards patients' characteristics, cut-off values, and follow-up time.

Keywords: Bladder carcinoma; CART; Ki-67,cell cycle regulators; Survival.