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Prognostic Implications of Molecular and Immunohistochemical Profiles of the Rb and p53 Cell Cycle Regulatory Pathways in Primary Non–Small Cell Lung Carcinoma

¹ Department of Pathology, Cork University Hospital, Cork, Ireland; ² Department of Pathology, New York Hospital/Cornell University Medical College, New York, New York; ³ Department of Pathology, Virginia Mason Clinic, Seattle, Washington; ⁴ Service de Pathologie Cellulaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; ⁵ Applied Research Branch, Cancer Surveillance Research Program; ⁶ Genetic Epidemiology Branch; ⁷ Laboratory of Pathology; and ⁸ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland; ⁹ Division of Human Genetics, City of Hope National Medical Center and Beckman Research Institute, Duarte, California; ¹⁰ Department of Pathology, University of Maryland, Baltimore, Maryland; ¹¹ Orrington, Maine; ¹² Department of Thoracic Surgery, Mayo Clinic Scottsdale, Scottsdale, Arizona; Departments of ¹³ Thoracic Surgery and ¹⁴ Pathology and ¹⁵ Thoracic Disease Division, Mayo Clinic, Rochester, Minnesota; and ¹⁶ Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, District of Columbia

Requests for reprints: Curtis C. Harris, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Building 37, Room 3068, Bethesda, MD 20892-4255. Phone: 301-496-2048; Fax: 301-496-0497; E-mail: Curtis_Harris{at}nih.gov.

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 overexpression 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 significantly 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.

Key Words: G₁ cyclins • p16^INK4A • p21^Waf1 • survival

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