Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours


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Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours
Lung Cancer
Gugger  M., Kappeler  A., Vonlanthen  S., Altermatt  H. J., Ris  H. B., Lardinois  D., Borner  M. M., Heighway  J., Betticher  D. C.
0169-5002 (Print)
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Journal Article
Research Support, U.S. Gov't, Non-P.H.S. --- Old url value: --- Old month value: Aug-Sep
Prognosis of lung cancer is related to stage of disease at time of diagnosis. In this study we examine alterations of pathways governing the cell cycle, in particular pRb-cyclinD1-p16 alpha and p53-p14ARF, in a series of NSCLC (n=92) at different stages at diagnosis. Using immunohistochemistry, we assessed the expression of the retinoblastoma protein (pRb), cyclin D1, p16 alpha, p53 and p14ARF. Tumours in stage I-IIIA (resectable) were more likely to have alterations in the pRb-cyclinD1-p16 alpha pathway than tumours in advanced stage (IIIB-IV) (90% versus 63%, P=0.002). pRb and p14ARF were more frequently downregulated in resectable tumours (P< or =0.03), and cyclin D1, p16 alpha, and p53 were altered at a similar frequency in resectable and advanced tumours. In 12 patients, metastatic sites (5 lymph node, 3 bone, 2 brain and 2 gastrointestinal metastases) were available for comparison with the primary tumour: 19 altered protein expressions were found to be concordant, six additional alterations (in 4 patients) were found in the metastases only, especially in lymph node metastases (3 patients). Compared with normal protein expression, both pathway alterations were associated with a longer survival (P=0.02). In a multivariate analysis (Cox regression) this difference was not maintained after adjustment for age, stage and tumour differentiation. Cyclin D1 was the sole protein with independent prognostic value in resectable tumours: the relative risk of local relapse was 4.7 in tumours without cyclin D1 overexpression (P=0.02, Cox regression analysis). No protein studied had a predictive significance for response after chemotherapy in non-resectable tumours. These results demonstrate a strong correlation between stage and pathway alterations, cell cycle regulators being less likely altered in advanced NSCLC. Tumours with defects in these control pathways tend therefore to remain localised and to metastasize at a later phase in tumour development. This finding might be an explanation for distinct biological behaviour (e.g. chemotherapy response) of resectable versus advanced disease.
Aged Carcinoma, Non-Small-Cell Lung/*metabolism/mortality/pathology Cell Cycle Cell Cycle Proteins/*metabolism Cell Nucleus/metabolism Cyclin D1/metabolism Cyclin-Dependent Kinase Inhibitor p16/metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins/metabolism Female Humans Immunoenzyme Techniques Lung Neoplasms/*metabolism/mortality/pathology Male Middle Aged Neoplasm Staging Prognosis Proteins/metabolism Retinoblastoma Protein/metabolism Survival Rate Tumor Suppressor Protein p14ARF Tumor Suppressor Protein p53/metabolism
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29/01/2008 13:59
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20/08/2019 14:29
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