Role of cdk4, p16, and Rb Expression in the Prognosis of Bronchioloalveolar Carcinomas.

Background: The p16^INK4 protein has been identified as a potent inhibitor of cyclin-dependent kinase (cdk)4 by blocking cdk4-mediated phosphorylation of the tumor suppressor retinoblastoma (Rb) protein, thus allowing Rb-mediated growth suppression. Objectives: Loss of p16^INK4 has been associated with a poor cancer prognosis, but its potential significance in bronchioloalveolar carcinomas (BACs) has not been explored. Methods: We examined immunohistochemical expression of p16^INK4, cdk4, and Rb proteins in 38 BACs and correlated their expression levels with known clinicopathological features of the disease. Results: All BACs expressed cdk4, while 89 and 82% expressed p16^INK4 and Rb proteins, respectively. None of the clinicopathological factors correlated with p16^INK4, cdk4, or Rb expression separately. A low p16^INK4/cdk4 ratio was significantly associated with a high disease stage (p = 0.04), and the ratio tended to be lower in mucinous than nonmucinous tumors. BACs with a low p16^INK4/cdk4 ratio showed significantly higher Rb expression levels (p = 0.02). Univariable survival analyses showed a significantly lower 5-year survival probability in patients with a high stage (p = 0.002) or low p16^INK4/cdk4 ratio (p = 0.01). Conclusions: The results suggest a role of the cdk4/p16^INK4 pathway in the prognosis of BACs. Further studies are warranted to clarify whether a low p16^INK4/cdk4 ratio may identify tumors that are destined to behave unfavorably.Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]