Loss of nuclear p27kip1 and α-dystroglycan is a frequent event and is a strong predictor of poor outcome in renal cell carcinoma

Expression levels of p27^kip1, a negative regulator of the G1 phase of the cell cycle, and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were assessed by immunostaining in a series of renal cell carcinomas (RCCs) and their prognostic significance was evaluated. Expression of p27^kip1 as well as of the α-subunit of the dystroglycan (DG) complex, previously reported to be altered in RCC, was also evaluated by western blot analysis. Nuclear expression of p27^kip1 was reduced in a significant fraction of tumors and low p27^kip1 staining correlated with higher tumor grade (P < 0.01). Recurrence and death from clear cell RCCs were significantly more frequent in p27^kip1-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (P = 0.011) and overall (P = 0.002) survival. Low nuclear expression of p27^kip1 as well as loss of α-DG were confirmed to be independent prognostic parameters at a multivariate analysis and the simultaneous loss of both molecules defined a high-risk group of patients with increased risk of recurrence (RR = 28.7; P = 0.01) and death (RR = 12.9; P = 0.03). No significant correlation with clinical or pathological parameters was found for 8-OHdG staining. Western blot analyses suggested a post-translational mechanism for the loss of α-DG expression and demonstrated that cytoplasmic dislocation of the protein contributes to the loss of active nuclear p27^kip1. Loss of nuclear p27^kip1 is a frequent event in human RCCs and is a powerful predictor of poor outcome which, in combination with low DG expression, could help to identify high-risk patients with clear cell RCC.