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Mutations of the MEN1 Tumor Suppressor Gene in Pituitary Tumors

Laboratory of Pathology, National Cancer Institute [Z. Z., A. O. V., W. S. P., S. P., S. H., L. V. D., M. R. E-B., L. A. L., I. A. L.], Surgical Neurology branch, National Institute of Neurological Disorders and Stroke [R. W., E. H. O.], Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases [S. K. A., M. B. K., C. H., A. L. B., A. M. S., S. J. M.], and Laboratory of Gene Transfer, National Human Genome Research Institute [S. C. G., P. M., J. S. C., S. C. C., F. S. C.], NIH, Bethesda, Maryland 20892; Department of Medicine, Wellesley Hospital, University of Toronto, Toronto, Ontario M4Y 1Y3, Canada [S. Z. Z.]; and Department of Pathology, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada [S. L. A.]

Although pituitary adenomas are monoclonal proliferations, somatic mutations involving genes that govern cell proliferation or hormone production have been difficult to identify. The genetic etiology of most pituitary tumors, therefore, remains unknown. Pituitary adenomas can develop sporadically or as a part of multiple endocrine neoplasia type 1 (MEN1). Recently, the gene responsible for MEN1 was cloned. To elucidate the potential etiological role of the MEN1 gene in pituitary tumorigenesis, 39 sporadic pituitary adenomas from 38 patients and 1 pituitary adenoma from a familial MEN1 patient were examined for MEN1 gene mutations and allelic deletions. Four of 39 sporadic pituitary adenomas showed a deletion of one copy of the MEN1 gene, and a specific MEN1 gene mutation in the remaining gene copy was detected in 2 of these tumors. The corresponding germ-line sequence was normal in all sporadic cases. A specific MEN1 mutation was detected in a pituitary adenoma and corresponding germ-line DNA in a patient with familial MEN1. An allelic deletion of the remaining copy of the MEN1 gene was also found in the patient's tumor. Genetic alterations of the MEN1 gene represent a candidate pathogenetic mechanism of pituitary tumorigenesis. The data suggest that somatic MEN1 gene mutations and deletions play a causative role in the development of a subgroup of sporadic pituitary adenomas.

¹ These authors contributed equally to this work.

² To whom requests for reprints should be addressed, at Laboratory of Pathology (I. A. L.), National Cancer Institute, NIH, Building 10, Room 2A33, 10 Center Drive, Bethesda, MD 20892; Phone: (301) 496-0549; Fax: (301) 402-0043; E-mail: lubensky@box-1.nih.gov; and at Department of Pathology (S. L. A.), Mt. Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada; Phone: (416) 586-8445; Fax: (416) 586-8589.

Received 9/22/97. Accepted 10/28/97.

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