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Trichoepitheliomas Contain Somatic Mutations in the Overexpressed PTCH Gene: Support for a Gatekeeper Mechanism in Skin Tumorigenesis¹

Igor Vrechovsk^2,3,, Anne Birgitte Undén³, Bengt Sandstedt, Rune Toftgård and Mona Ståhle-Bäckdahl

Karolinska Institute, Department of Biosciences at Novum, S-14157 Huddinge, Sweden [I. V., A. B. U., R. T.]; Royal Free Hospital School of Medicine, University of London, London NW3 2PF, United Kingdom [I. V.]; and Departments of Pathology [B. S.] and Dermatology [A. B. U., M. S. B.], Karolinska Hospital, S-17176 Stockholm, Sweden

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility. NBCCS is caused by mutations in the human homologue (PTCH) of the Drosophila patched gene, a developmental regulator implicated in signaling of hedgehog and smoothened. The PTCH gene was found to contain somatic mutations also in sporadic basal cell carcinomas and medulloblastomas, tumors seen in NBCCS, consistent with PTCH acting as a tumor suppressor. Because basal cell carcinomas have been observed to develop in association with benign trichoepitheliomas (TEs) in the same lesions, patients, and families and may share the same cell of origin, we have analyzed PTCH for mutations and expression in TEs. We report frameshift and in-frame somatic deletions in this gene and a consistent overexpression of PTCH mRNA in TEs. These findings provide the first evidence of a gene mutation in TEs and identify a common pathogenic pathway for histopathologically similar but prognostically distinct skin tumors. Moreover, these results support the presence of a gatekeeper mechanism in multistep skin tumorigenesis exerted by the altered PTCH signaling pathway.

¹ This work was supported by the Karolinska Institute, the Swedish Radiation Protection Institute, the Swedish Cancer Fund, the Swedish Children Cancer Fund, Cancerföreningen, Welander-Finsen Foundation, and the British Medical Research Council.

² To whom requests for reprints should be addressed, at Karolinska Institute, Centre for Biotechnology, Hälsovägen 7, S-14157 Huddinge, Sweden. Phone: 46-8-6089269; Fax: 46-8-7745538; E-mail: igor.vorechovsky@cbt.ki.se.

³ The first two authors contributed equally to this study.

Received 7/ 9/97. Accepted 9/22/97.

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