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Somatic Mutations of the RET Proto-oncogene Are Not Required for Tumor Development in Multiple Endocrine Neoplasia Type 2 (MEN 2) Gene Carriers¹

Departments of Internal Medicine [R. M. L., M. J. d. W., R. A. Z., J. W. M. H., C. J. M. L.] and Pathology [R. M. L., M. J. d. W., R. A. Z. J. W. M. H.], University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands; Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, the Netherlands [R. M. W. H., C. H. C. M. B.]; and DNA Laboratory, Clinical Genetics Center Utrecht, P. O. Box 85500, 3508 GA Utrecht, the Netherlands [H-K. P. v. A.]

Germ line mutations in one allele of the RET proto-oncogene predispose to the multiple endocrine neoplasia type 2 (MEN 2) syndromes. To investigate whether these inherited mutations alone can cause the development of tumors in vivo (oncogene model) or whether somatic mutations in the homologous RET allele are required for tumorigenesis (tumor suppressor gene model), we analyzed the entire coding region of both alleles of the RET gene in two MEN 2A and two MEN 2B tumors by reverse transcription-PCR and direct sequencing. No tumor-specific mutations could be detected in either allele of the RET gene in these tumors. Unlike the molecular mechanism in other hereditary tumor syndromes, somatic mutations in the homologous allele are apparently not required in MEN 2 tumorigenesis. Thus, RET genes with MEN 2-specific germ line mutations act as dominantly transforming oncogenes in vivo.

¹ Supported by Grant 28-1367-2 from the Prevention Fund, the Netherlands (to R. M. L., M. J. d. W., R. A. Z.) and Grant 91-14 from the Dutch Cancer Society (to R. M. W. H.).

² To whom requests for reprints should be addressed, at Department of Pathology H04.313, University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. Phone: 31-302506557; Fax: 31-302544990; E-mail: R.M.Landsvater@lab.azu.nl.

Received 7/30/96. Accepted 9/19/96.

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