p21(waf1/cip1) and transforming growth factor β1 protein expression correlate with survival in non-small cell lung cancer

William P. Bennett, Wafik S. El-Deiry, Walter L. Rush, Donald G. Guinee, Andrew N. Freedman, Neil E. Caporaso, Judith A. Welsh, Raymond T. Jones, Andrew Borkowski, William D. Travis, Marian V. Fleming, Victor Trastek, Peter C. Pairolero, Henry D. Tazelaar, David Midthun, James R. Jett, Lance A. Liotta, Curtis C. Harris

Research output: Contribution to journalArticlepeer-review

Abstract

p21(waf1/cip1) encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor β1 (TGF-β1), AP2, and other pathways. Because p21(waf1/cip1), p53, and TGF-β1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21(waf1/cip1) and TGF-β1 and identified four patient groups with distinct survival outcomes. Concordant p21(waf1/cip1) and TGF-β1 expression (i.e., either high p21(waf1/cip1) and high TGF-βI expression or low p21(waf1/cip1) and low TGF- β1 expression) predicted 70% disease-free survival at 2000 days of follow- up. Discordant p21(waf1/cip1) and TGF-β1 expression (i.e., either high p21(waf1/cip1) and low TGF-β1 expression or low p21(waf1/cip1) and high TGF- β1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable 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- β1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21(waf1/cip1) protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21(waf1/cip1) protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21(waf1/cip1) protein. These findings indicate that p21(waf1/cip1) immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.

Original languageEnglish (US)
Pages (from-to)1499-1506
Number of pages8
JournalClinical Cancer Research
Volume4
Issue number6
StatePublished - Jun 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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