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BAX and p16^INK4A are independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer

¹ Dept of Internal Medicine, Pneumology, University of Leipzig, Germany, ² Dept of Pneumology, Div. of Internal Medicine, University Hospital Charité, Humboldt University of Berlin, Germany, ³ Institute of Pathology, University of Leipzig, Germany, ⁴ Theragen AG, Biomedical Research Campus, Berlin-Buch, Germany, and ⁵ Max Delbrueck Centrum for Molecular Medicine Berlin-Buch, Germany

CORRESPONDENCE: C. Gessner, Dept of Internal Medicine, Pulmonary unit, Johannisallee 32, 04103, Leipzig, Germany. Fax: 49 3419712609

Keywords: apoptosis, BAX, p16^INK4A, p53, prognosis, survival

Received: February 28, 2001
Accepted August 7, 2001

Clinical studies suggest prognostic relevance of p16^INK4A in nonsmall cell lung cancer (NSCLC) while conflicting results for p53 have been published. However, the importance of the apoptosis regulating gene BAX, a downstream regulator of p53, on the prognosis of NSCLC is unknown. The present study investigated the prognostic relevance of BAX with respect to the status of p53 and p16^INK4A in 61 patients with advanced NSCLC.

Protein expression of BAX, p53 and p16^INK4A was investigated retrospectively by immunohistochemistry. Tumour deoxyribonucleic acid (DNA) was screened for p53 mutations by single strand-conformation polymorphism polymerase chain reaction (PCR) and BAX frameshift mutations by fragment length analysis.

Patients with positive BAX protein expression had a significantly longer median survival (14 months) than those patients without BAX expression (6 months, p=0.0004). In contrast, p53 status did not influence prognosis. Patients with p16^INK4A negative tumours had a significantly shorter survival (4 months) than those with p16^INK4A protein expression (15 months, p=0.0001). Furthermore, the loss of p16^INK4A protein expression correlated strongly with the pressure of distant and advanced lymph-node metastases. The best survival was seen in a subgroup of 20 patients with positive p16^INK4A expression and intact BAX (p=0.0002).

The results of the present study suggest that the loss of BAX and p16^INK4A expression are independent markers for poor prognosis in nonsmall cell lung cancer. The study suggests that multimarker analysis of genes involved in apoptosis may be useful for determining individual therapy and for identifying targets for gene-replacement therapy. This should be assessed in a prospective study with a larger cohort of patients.