Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma

Louise Burke, Douglas B. Flieder, Donald G. Guinee, Elizabeth Brambilla, Andrew N. Freedman, William P. Bennett, Raymond T. Jones, Andrew Borkowski, Neil A. Caporaso, Marian Fleming, Victor Trastek, Peter Pairolero, Henry Tazelaar, David Midthun, James R. Jett, Lance A. Liotta, William D. Travis, Curtis C. Harris

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16 INK4A, and pRb) or the p53 (p53 and p21 Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21 Waf1, pRb, p16 INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. Results: Cyclin D1 overespression was noted in 48% of the tumors, p16 INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21 Waf1 overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a signifiqantly poorer prognosis (P = 0.0033 and 0.0063, respectively). Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.

Original languageEnglish (US)
Pages (from-to)232-241
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number1
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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