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Rb and p16^INK4a Expression in Resected Non-Small Cell Lung Tumors¹

Department of Medicine, Sections of Hematology/Oncology [R. A. K.] and Pulmonary Medicine [T. M. G., J. B. R., D. E. N.], and Departments of Pathology [G. A. N.] and Surgery [M. A. M.], Minneapolis Veterans Affairs Medical Center and the University of Minnesota Medical School, Minneapolis, Minnesota 55417, and Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 [J. G.]

Inactivation of the cyclin-dependent kinase inhibitor p16^INK4a (CDKN2/MTS1) is documented in a wide variety of cancer cell lines and tumors. We have shown that loss of p16^INK4a protein expression is a common event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher stage disease. One hundred NSCLC tumors from patients undergoing definitive 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^INK4a protein expression. Tumors with aberrant expression of p16^INK4a by immunohistochemistry were associated with a significantly worse survival (P = 0.04). Additionally, the inverse correlation of pRB and p16^INK4a expression previously noted in lung cancer cell lines and tumors was confirmed in this large cohort of patients, with 65% of the tumors demonstrating inverse expression of pRB and p16^INK4a (P = 0.00019). A statistically significant increase in aberrant p16^INK4a expression, as well as inverse expression of p16^INK4a and pRB, was seen with increasing pathological stage of disease. These findings establish the prognostic significance of the absence of p16^INK4a in resected NSCLC and confirm the critical importance of disrupting the pathway of cyclin-dependent kinase-mediated phosphorylation of pRB in the molecular oncogenesis and progression of NSCLC.

¹ This work was supported by a Research Advisory Group grant from the Department of Veterans Affairs (R. A. K.).

² To whom requests for reprints should be addressed, at Section of Hematology/Oncology, 111E, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417. Phone: (612) 725-2000, ext. 4135; E-mail: kratzke.robert@minneapolis.va.gov.

Received 5/ 7/96. Accepted 6/14/96.

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