Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in renal cell carcinoma

Abstract

e16008 Background: Deregulation of the normal cell cycle is a frequent event in human tumors and plays an important role in malignant transformation. p27kip1 is a negative regulator of the G1 phase, is frequently lost in tumor cells and, in some cases, its alteration is coupled with oxidative DNA damage. Methods: We evaluated the expression of p27kip1 and the extent of endogenous oxidative DNA damage (by means of 8-hydroxydeoxyguanosine [8-OHdG] levels) by immunostaining in a series of 125 (median age 64[range23–86]yrs) renal cell carcinomas (RCCs); furthermore, the prognostic significance of their alterations was tested. Median values of expression were used as cut-off. p27kip1 expression was also evaluated by Western Blot in a second series of 34 fresh-frozen RCCs. Results: to date, median follow-up is 29[range 4 - 104] months. p27kip1expression was lost in a significant fraction of tumors (55%) with a median percentage of positive cells of 20% [range 0–60%). Loss of p27kip1 staining correlated with higher tumor grade (p=0.049). Recurrence (p=0.007) and death (p=0.006) from RCCs were significantly more frequent in patients p27kip1-negative compared with positive ones. Kaplan-Meier analysis showed a significant separation between high vs low p27kip1 expression groups for both disease-free (p=0.011) and overall (p=0.002) survival. At multivariate analysis, loss of p27kip1expression was the only independent risk predictor for recurrence (HR=4.326, p=0.014) and death (HR=4.915, p=0.012) from RCCs when tumor size, tumor grade and stage were included. No significant correlation with clinical or pathological parameters and outcome was found for 8- OHdG. p27kip1 total protein levels showed a variable behaviour at WB analysis with a modest trend toward a global reduction but an elevation in some cases. Conclusions: loss of p27kip1 is frequent in human RCCs and is a powerful predictor of poor outcome. p27kip1 alteration are not related to endogenous oxidative DNA damage. The behaviour of p27kip1at WB analysis is probably related to the elevation of the cytoplasmatic (and inactive) fraction. No significant financial relationships to disclose.