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P53 Mutation Analysis of Colorectal Liver Metastases: Relation to Actual Survival, Angiogenic Status, and p53 Overexpression

Authors' Affiliations: ¹ Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of Surgery and ² Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands

Requests for reprints: Koert P. de Jong, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, the Netherlands. Phone: 31-50-3612896; Fax: 31-50-3614873; E-mail: k.p.de.jong{at}chir.umcg.nl.

Purpose: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations.

Experimental Design: Tumors of 44 patients with surgically treated colorectal liver metastases were analyzed for (a) TP53 mutations using denaturing gradient gel electrophoresis followed by sequencing, (b) microvessel density using the hot spot overlap technique, (c) apoptotic rate in tumor cells and endothelial cells of tumor microvessels using double immunostaining for anti–cleaved caspase 3 and anti-CD34, and (d) expression of p53 protein using immunohistochemistry.

Results: TP53 mutations were detected in 36% of the metastases and occurred more frequently in liver metastases from left-sided colon tumors than from right-sided colon tumors (P = 0.04). In metastases with TP53 mutations, microvessel density was higher compared with tumors with wild-type p53. Endothelial cell apoptosis was not different in tumor microvessels from TP53-mutated versus nonmutated tumors. The 5-year actual survival was not influenced by TP53 mutational status, microvessel density, or endothelial cell apoptotic rate of the tumors. Based on immunohistochemical p53 overexpression, the positive and negative predictive values of TP53 mutations were 61% and 82%.

Conclusions: In patients with surgically treated colorectal liver metastases, TP53 mutations and angiogenic status did not influence prognosis. Immunohistochemistry is not a reliable technique for detecting TP53 mutations.

Key Words: prognostic factors • partial hepatectomy • apoptosis

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