This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by SCHULTE, H. M. Articles by ALI, I. U. Search for Related Content PubMed PubMed Citation Articles by SCHULTE, H. M. Articles by ALI, I. U.

Clonal Composition of Pituitary Adenomas in Patients with Cushing's Disease: Determination by X-Chromosome Inactivation Analysis^*

HEINRICH M. SCHULTE, EDWARD H. OLDFIELD, BRUNO ALLOLIO, DAVID A. KATZ, RICHARD A. BERKMAN and IQBAL UNNISA ALI

Molecular Biology Laboratory, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, Maryland 20892

Address requests for reprints to: Dr. Heinrich M. Schulte, c/o Ms. Juliet Ellis, Surgical Neurology Branch/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10/Room 5D37, 9000 Rockville Pike, Bethesda, Maryland 20892.

The synthesis and secretion of anterior pituitary hormones are subjected to a variety of positive and negative feedback mechanisms. Aberrancies of these highly regulated phenomena may lead to hyperplasia involving multiple cells of the anterior lobe. Alternatively, a rare genetic mutation in a single cell may precede its clonal expansion. Which of these mechanisms is operative in the development of corticotroph adenomas is not known. To examine this question, we studied the clonal composition of ACTH-producing pituitary adenomas from female patients with Cushing's disease by using X-chromosome inactivation analysis. Nine of 27 patients examined were heterozygous at 1 of the 2 X-chromosome-linked polymorphic loci, hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase. The methylation patterns of the hypoxanthine- phosphoribosyl-transferase and phosphoglyceratekinase genes, distinguishing between the active and inactive alleles, were analyzed in DNA extracted from the central part of the tumor and compared with those of autologous lymphocyte DNA. Six tumors (4 microadenomas and 2 macroadenomas) showed a single active allele of the X-chromosome-linked genes and were monoclonal in nature. The other 3 pituitary adenomas (1 microadenoma and 2 macroadenomas, 1 from a patient with Nelson's syndrome) revealed a polyclonal pattern of X-chromosome inactivation.

Our data demonstrate that corticotroph adenomas of the pituitary may arise from a single cell or from more than one cell. Whether fundamentally different endocrine mechanisms underlie the two processes remains to be seen.

^* Presented in part at the 72nd Annual Meeting of The Endocrine Society, Atlanta, GA, 1990.

Heisenberg- Stipendiat of the Deutsche Forschungsgemeinschaft (Schu 669/1-1); current address: I. Medizinische Klinik, Christian-Albrechts-Universitat zu Kiel, Schittenhelmstr. 12, D-2300 Kiel, Germany.

Current address: Medizinische Klinik II der Universitat zu Koln, Germany.

Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Received September 26, 1990.

This article has been cited by other articles:

				L. Jovanovic, B. Delahunt, B. McIver, N. L. Eberhardt, and S. K. G. Grebe Thyroid Gland Clonality Revisited: The Embryonal Patch Size of the Normal Human Thyroid Gland Is Very Large, Suggesting X-Chromosome Inactivation Tumor Clonality Studies of Thyroid Tumors Have to Be Interpreted with Caution J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3284 - 3291. [Abstract] [Full Text] [PDF]

				R. N. Clayton, M. Pfeifer, A. B. Atkinson, P. Belchetz, J. A. H. Wass, E. Kyrodimou, M. Vanderpump, D. Simpson, J. Bicknell, and W. E. Farrell Different Patterns of Allelic Loss (Loss of Heterozygosity) in Recurrent Human Pituitary Tumors Provide Evidence for Multiclonal Origins Clin. Cancer Res., October 1, 2000; 6(10): 3973 - 3982. [Abstract] [Full Text]

				B. Xu, T. Sano, S. Yamada, C. C. Li, and M. Hirokawa Expression of Corticotropin-Releasing Hormone Messenger Ribonucleic Acid in Human Pituitary Corticotroph Adenomas Associated with Proliferative Potential J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1220 - 1225. [Abstract] [Full Text]

				P. L. M. Dahia and A. B. Grossman The Molecular Pathogenesis of Corticotroph Tumors Endocr. Rev., April 1, 1999; 20(2): 136 - 155. [Abstract] [Full Text]

				S. L. Asa and S. Ezzat The Cytogenesis and Pathogenesis of Pituitary Adenomas Endocr. Rev., December 1, 1998; 19(6): 798 - 827. [Abstract] [Full Text]

				K. D. Dieterich, E. D. Gundelfinger, D. K. Lüdecke, and H. Lehnert Mutation and Expression Analysis of Corticotropin-Releasing Factor 1 Receptor in Adrenocorticotropin-Secreting Pituitary Adenomas J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3327 - 3331. [Abstract] [Full Text]

				I. Shimon and S. Melmed Pituitary Tumor Pathogenesis J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 1675 - 1681. [Full Text] [PDF]