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The High Mobility Group A2 Gene Is Amplified and Overexpressed in Human Prolactinomas¹

Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, 20123 Milan, Italy [P. F., D. G., O. R., E. V., L. L.]; Dipartimento di Biologia e Patologia Cellulare e Molecolare, c/o Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy [G. M. P., M. F., A. F.]; Department of Neurosurgery, Ospedale San Raffaele, 20132 Milan, Italy (M. L., P. M.); Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [C. M. C.]; Department of Biology Genetics, University of Milan, 20133 Milan, Italy [L. L.]

Trisomy of chromosome 12 is a nonrandom chromosomal change in pituitary adenomas, particularly prolactinomas. This and the finding that prolactin-secreting pituitary adenomas develop in transgenic mice overexpressing the wild-type HMGA2 gene (which maps to 12q14–15) prompted us to investigate HMGA2 rearrangements and expression in human prolactinomas. By dual-color interphase fluorescence in situ hybridization analysis using HMGA2-specific PACs and BACs, we found that the HMGA2 locus was amplified in seven of the eight prolactinoma samples examined. The cytogenetic manifestations of elevated HMGA2 concentrations ranged from simple trisomy to tetrasomy 12 and der(12) chromosomes to marker chromosomes bearing 12q14–15-derived regions. Reverse transcription-PCR, Western blot and immunohistochemical analysis showed HMGA2 overexpression in a number of prolactinomas bearing rearrangement of regions 12q14–15. These data suggest a critical role of the HMGA2 overexpression in the generation of prolactin-secreting pituitary adenomas in humans.

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