P21(WAF1 CIP1) AND TRANSFORMING-GROWTH-FACTOR BETA-1 PROTEIN EXPRESSION CORRELATE WITH SURVIVAL IN NONSMALL CELL LUNG-CANCER/

p2l(waf1/cip1) encodes a cyclin-dependent kinase inhibitor that is tra nscriptionally activated by the p53 tumor suppressor gene, transformin g growth factor beta 1 (TGF-beta 1), AP2, and other pathways, Because p21(waf1/cip1), p53, and TGF-beta 1 all regulate apoptosis and the cel l cycle, we tested the hypothesis that their relative protein levels w ould correlate ,vith biological features including the survival of non -small cell lung cancer (NSCLC) patients. We conducted an immunohistoc hemical analysis of p21(waf1/cip1) and TGF-beta 1 and identified four patient groups with distinct survival outcomes, Concordant p2l(waf1/ci p1) and TGF-beta 1 expression (i.e., either high p2l(waf1/cip1) and hi gh TGF-beta 1 expression or low p21(waf1/cip1) and low TGF-beta 1 expr ession) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p2l(waf1/cip1) and TGF-beta 1 expression (i.e., either hig h p2l(waf1/cip1) and low TGF-beta 1 expression or low p21(waf1/cip1) a nd high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attrib utable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC su rvival. In addition to the survival correlation, we found that high p2 1(waf1/cip1) protein expression correlated with high tumor grade (P = 0.014), There is little evidence that p2l(waf1/cip1) protein levels ac curately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p2l(waf1/cip1 ) protein, These findings indicate that p2l(waf1/cip1) immunohistochem ical analysis may provide useful information concerning the biological properties of NSCLC.