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Analysis of p53/BAX/p16^ink4a/CDKN2 in Esophageal Squamous Cell Carcinoma: High BAX and p16^ink4a/CDKN2 Identifies Patients With Good Prognosis

From the Department of Hematology, Oncology and Tumor Immunology, Charité - Campus Berlin-Buch, Humboldt University; Invitek GmbH; Theragen AG; and Max Delbrück Center for Molecular Medicine, Berlin-Buch; Institute of Pathology, Charité - Campus Berlin-Mitte, Berlin; and Department of General and Vascular Surgery, University Hospital, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.

Address reprint requests to Peter Daniel, MD, Department of Hematology, Oncology and Tumor Immunology, Charité - Campus Berlin-Buch, Humboldt University, Lindenberger Weg 80, 13125 Berlin-Buch, Germany; email: pdaniel{at}mdc-berlin.de

PURPOSE: We have previously shown that loss of BAX expression is a negative prognostic factor in metastatic colorectal cancer. In the present study, we addressed the prognostic relevance of BAX and its upstream regulator p53 in squamous cell carcinoma (SCC) of the esophagus. Analysis of p16^ink4a/CDKN2 was included because p16^ink4a/CDKN2 and p53 were shown previously to cooperate during induction of cell cycle arrest and apoptosis.

PATIENTS AND METHODS: Retrospective analysis of 53 patients with curative intended R0 resection of esophageal SCC was done. Protein expression of BAX, p53, and p16^ink4a/CDKN2 was investigated by immunohistochemistry. In addition, tumor DNA was screened for BAX frameshift mutations by fragment length analysis and for p53 mutations by single-strand conformation polymorphism–polymerase chain reaction.

RESULTS: Overall median survival was 13.7 months. Patients with high BAX protein expression had a median survival of 19.5 months versus 8.0 months with low BAX expression (P < .005). High p16^ink4a/CDKN2 protein expression was associated with a median survival of 23.8 months versus 9.7 months with low p16^ink4a/CDKN2 (P = .011). The best survival (median, 45.8 months) was seen in a subgroup of 12 patients whose tumors bore the combination of both favorite phenotypes (ie, high BAX and high p16^ink4a/CDKN2 protein expression).

CONCLUSION: In this retrospective investigation, the combined analysis of BAX and p16^ink4a/CDKN2 shows subgroups in SCC of the esophagus with favorable (p16^ink4a/CDKN2/BAX high expressing) or poor prognosis (loss of p16^ink4a/CDKN2/loss of BAX). We suggest that such a multimarker analysis of apoptosis pathways could be useful for individualization of therapeutic strategies in the future, and suggest prospective studies to confirm these results.

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