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| AP2β Nucleolar Localization Predicts Poor Survival After Lung Cancer Resection in Stage I Patients |
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Min P. Kim1, Ying Chen2, Adriana Lopez3, Ignacio Wistuba2, Lin Ji1, Jack A. Roth1, Ruth L. Katz2; 1 Thoracic and Cardiovascular Surgery, M.D. Anderson Cancer Center, Houston, TX; 2 Pathology, M.D. Anderson Cancer Center, Houston, TX; 3 Biostatistics, M.D. Anderson Cancer Center, Houston, TX Objective: Activating enhancer-binding protein-2β (AP2β) is a nuclear transcription factor that activates human telomerase reverse transcriptase (hTERT) expression. It was recently shown that up-regulation of AP2β leads to increased telomerase expression, whereas down regulation of AP2β inhibits both telomerase activity and tumor cell growth. We hypothesized that AP2β expression may be a predictor of poor survival in lung cancer patients. Methods: Immunohistochemistry staining (IHC) for AP2β was performed on tissue microarrays prepared from resected stage I NSCLC from126 patients. There were two distinct patterns of staining: 1) diffuse nuclear staining; 2) nucleolar staining characterized by staining of nucleoli, with or without diffuse nuclear staining. The staining pattern and IHC intensity score were correlated with prospectively collected clinical data. Validation was performed with a non-overlapping group of 115 stage I NSCLC patients. Results: IHC confirmed co-localization of telomerase and AP2β in lung cancer cells. The IHC intensity score did not correlate with the stage, survival, tumor differentiation, or histology. The patients with a nucleolar pattern had a significantly worse five-year survival (67%) compared to patients with a diffuse nuclear pattern (100%, p=0.009). Multivariate analysis showed that nucleolar AP2β pattern (p=0.004, HR 13.9, CI 1.9-1782.1) was an independent predictor for poor survival. The validation set confirmed that patients with a nucleolar pattern had a significantly worse five-year survival (64%) compared to patients with a diffuse nuclear pattern (91%, p=0.02). Multivariate analysis of the validation set confirmed that the nucleolar AP2β pattern (p=0.037, HR 2.18, CI 1.05-4.51) was an independent predictor for poor survival. Conclusion: Genome wide mRNA or proteomic expression array analysis would not have identified the prognostic significance of AP2β since the expression level of the AP2β protein did not correlate with survival. The movement of telomerase to nucleoli is a response to DNA damaging agents and prevents inappropriately added telomere ends during DNA replication. A possible explanation for our results is that tumor cells that maintain AP2β and hTERT in the nucleoli may be more aggressive due to resistance to DNA damage. We conclude that AP2β localization may be a useful biomarker for predicting survival in stage I NSCLC, and that intracellular protein localization should be considered in the evaluation of prognostic biomarkers.  The stage I lung cancer patients with nucleolar pattern had significantly worse five year survival (67%) compare to patients with diffuse pattern (100%) Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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