RB AND P16(INK4A) EXPRESSION IN RESECTED NONSMALL CELL LUNG-TUMORS

Inactivation of the cyclin-dependent kinase inhibitor p16(INK4a) (CDKN 2/ MTS1) is documented in a wide variety of cancer cell lines and tumo rs. We have shown that loss of p16(INK4a) protein expression is a comm on event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher sta ge disease. One hundred NSCLC tumors from patients undergoing definiti ve thoracotomies at a single institution were examined for p16(INK4a) and retinoblastoma protein (pRB) expression. Abnormal pRB staining was identified in 15% of the tumors, whereas 51% possessed aberrant p16(I NK4a) protein expression. Tumors with aberrant expression of p16(INK4a ) by immunohistochemistry were associated with a significantly worse s urvival (P = 0.04). Additionally, the inverse correlation of pRB and p 16(INK4a) expression previously noted in lung cancer cell lines and tu mors was confirmed in this large cohort of patients, with 65% of the t umors demonstrating inverse expression of pRB and p16(INK4a) (P = 0.00 019). A statistically significant increase in aberrant p16(INK4a) expr ession, as well as inverse expression of p16(INK4a) and pRB, was seen with increasing pathological stage of disease. These findings establis h the prognostic significance of the absence of p16(INK4a) in resected NSCLC and confirm the critical importance of disrupting the pathway o f cyclin-dependent kinase-mediated phosphorylation of pRB in the molec ular oncogenesis and progression of NSCLC.