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Novel Molecular Signaling and Classification of Human Clinically Nonfunctional Pituitary Adenomas Identified by Gene Expression Profiling and Proteomic Analyses

¹ Department of Pathology and Laboratory Medicine and Winship Cancer Institute and ² Department of Neurosurgery and Laboratory of Molecular Neurosurgery and Biotechnology, Emory University School of Medicine, Atlanta, Georgia; ³ Charles B. Stout Neuroscience Mass Spectrometry Laboratory and Departments of ⁴ Neurology and ⁵ Molecular Sciences, University of Tennessee, Health Science Center, and University of Tennessee Cancer Institute, Tennessee; and ⁶ Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, Alabama

Requests for reprints: Nelson M. Oyesiku, Department of Neurosurgery, Emory University School of Medicine, 1365-B Clifton Road Northeast, Suite 6400, Atlanta, GA 30322. Phone: 404-778-4737; Fax: 404-778-4472; E-mail: noyesik{at}emory.edu.

Pituitary adenomas comprise 10% of intracranial tumors and occur in about 20% of the population. They cause significant morbidity by compression of regional structures or the inappropriate expression of pituitary hormones. Their molecular pathogenesis is unclear, and the current classification of clinically nonfunctional tumors does not reflect any molecular distinctions between the subtypes. To further elucidate the molecular changes that contribute to the development of these tumors and reclassify them according to the molecular basis, we investigated 11 nonfunctional pituitary adenomas and eight normal pituitary glands, using 33 oligonucleotide GeneChip microarrays. We validated microarray results with the reverse transcription real-time quantitative PCR, using a larger number of nonfunctional adenomas. We also used proteomic analysis to examine protein expression in these nonfunctional adenomas. Microarray analysis identified significant increases in the expression of 115 genes and decreases in 169 genes, whereas proteomic analysis identified 21 up-regulated and 29 down-regulated proteins. We observed changes in expression of SFRP1, TLE2, PITX2, NOTCH3, and DLK1, suggesting that the developmental Wnt and Notch pathways are activated and important for the progression of nonfunctional pituitary adenomas. We further analyzed gene expression profiles of all nonfunctional pituitary subtypes to each other and identified genes that were affected uniquely in each subtype. These results show distinct gene and protein expression patterns in adenomas, provide new insight into the pathogenesis and molecular classification of nonfunctional pituitary adenomas, and suggest that therapeutic targeting of the Notch pathway could be effective for these tumors.

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