Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma

Abstract

Context: Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown.

Objective: The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome.

Patients and methods: A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes.

Results: In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed.

Conclusions: We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.

Fig. 1.

Microarray signal values and relative expression measured by real-time PCR for the genes FOS, GNAS, GADD45A, AKAP9, and NTS. Dotted lines indicate the expression of the corresponding genes in normal pituitaries. A, Studies performed in the MEN1-associated pituitary tumor, showing concordance with the expression pattern observed in microarray analysis, for all genes evaluated. B, Results from the sporadic pituitary adenoma. Except for GADD45A, the pattern of gene expression observed in microarray was confirmed by real-time PCR.

Fig. 2.

Immunohistochemical analysis for Ptx2, cFos, and Gsα proteins. A, Immunostaining was negative for Ptx2 in both the MEN1-associated and the sporadic pituitary tumor. In contrast, cFos (B) and Gsα (C) were expressed in the MEN1-associated but negative in the sporadic pituitary tumor.