Cell cycle regulators in bladder cancer: A multivariate survival study with emphasis on p27Kip1

Cyclin-dependent kinase inhibitors (CKIs) prevent cyclin-dependent kinases from phosphorylating critical substrates such as retinoblastoma gene protei n (pRb), hence blocking the cascade of events leading to cell proliferation . Currently, the list of CKIs includes p21WAF1/Cip1, p27Kip1, p57Kip2 (the Cip/Kip family), p15/INK4b, p16/INK4a, p18/INK4c, and p19/INK4d (the INK4 f amily). Among them, p27 plays a crucial role inning extracellular growth-re gulatory signals to progression to or exit from the cell cycle. Unlike p53, p16, and Rb, mutations in Kip1 and WAF1 genes are distinctly rare in bladd er cancer. We analyzed immunohistochemically the expression of p27 and othe r interacting G1 proteins (ie, p21, p16, pRb, p53) in 120 consecutive cases of transitional cell carcinomas (TCCs) and related it to proliferation rat e, clinicopathologic parameters, and survival. p27 levels were significantl y higher in low-grade (P = .001), superficial (Ta-T1) (P = .001), papillary (P < .001), and slowly proliferating TCCs (r(s) = -0.235, P = .05). p27 al so positively correlated with p16 expression (r(s) = 0.212, P = .05). In un ivariate analysis, decreased p27 expression was associated with poor overal l (P = .0100) and postrelapse (P = .0344) survival, especially if combined to increased Ki-67 expression (P = .0004 and P = .036, respectively). Furth ermore, in multivariate analysis, Ki-67/p27 status had the strongest hearin g on the overall survival of muscle-invasive TCCs (P = .0019). Our results indicate that low p27 expression is more common in poorly differentiated mu scle-invasive TCCs and is a major player in cell cycle control in these neo plasms. More importantly, the combined Ki-67/p27 expression provides progno stic information beyond that provided by conventional parameters or other c ell cycle-related proteins, concerning overall survival in muscle-invasive TCCs. HUM PATHOL 31:751-760. Copyright (C) 2000 by W.B. Saunders Company.