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Expression of Mutated p53 Occurs in Tumor-distant Epithelia of Head and Neck Cancer Patients: A Possible Molecular Basis for the Development of Multiple Tumors¹

Molecular Biology Laboratory, Ear, Nose, and Throat University Hospital, 69120 Heidelberg, Germany

As in most other tumor types, expression of mutated or phenotypically altered p53 is a common occurrence in head and neck carcinogenesis. Since the prognosis for many head and neck tumor patients is severely affected by the occurrence of multiple primary and secondary tumors, we have analyzed the phenotype and genotype of p53 in squamous and respiratory epithelia either adjacent to or at significant distance from the primary tumors. Many tumor patients showed multifocal overexpression of the p53 protein in a variety of these epithelia. Overexpression of p53 correlated with increased proliferation and dedifferentiation, as demonstrated by immunohistochemistry and in situ hybridization using histone H3 and cytokeratin-specific probes. Polymerase chain reaction-singlestrand conformation polymorphism analysis and sequencing of p53 DNA, amplified from these biopsies after immunostaining and microdissection, confirmed and extended these findings. We have identified different mutations in p53 in different tumor-distant epithelia from the same patients. The data indicate that mutation of p53 is an early event in head and neck carcinogenesis, preceding signs of overt neoplasia, and that different mutations in p53 in multiple foci may provide a molecular basis for the development of multiple tumors.

¹ This work was supported by grants from the Verein zur Förderung der Krebsforschung in Deutschland e.V. and the Tumorzentrum Heidelberg/Mannheim.

² To whom requests for reprints should be addressed, at Molecular Biology Laboratory, Ear, Nose and Throat University Hospital, W-6900 Heidelberg, Germany.

Received 3/31/93. Accepted 7/ 8/93.

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