Background: Familial isolated pituitary adenoma (FIPA) is recently identified autosomal dominant condition with incomplete penetrance. Heterozygote mutations have been identified in the aryl-hydrocarbon receptor interacting protein (AIP) gene in 2030% of FIPA families. AIP mutation positive patients have distinct phenotype: the disease is occurring at a younger age and have more aggressive tumours.
Aims: The aim of this study was to perform comparative gene expression analysis of AIP positive, AIP negative and sporadic tumours to discover the genes/pathways responsible for the AIP positive phenotype and to understand the underlying molecular mechanisms involved in the pituitary tumorigenesis.
Methods: We have performed gene expression analysis on normal pituitary, sporadic GH-secreting adenomas, AIP positive and AIP negative familial somatotroph adenomas (five samples of each category) using the Affymetrix human Gene Chip HG-U133 Plus 2.0 array. Data analysis was carried out in the statistical R environment. Ingenuity pathway analysis (IPA) tool was used for pathway analysis. Expression of the five selected genes from microarray analysis was validated by quantitative reverse transcriptase PCR.
Results: We have identified a large number of differentially expressed genes in pituitary adenomas compared to normal pituitary. In addition, a small number of genes differ in their expression levels between familial AIP positive and sporadic adenomas. These genes are involved in epithelial-to-mesenchymal transition (EMT), extra-cellular matrix (ECM) remodelling and cellular invasion. QRT-PCR data of the increased expression of mesenchymal marker, invasive markers and the decreased expression of epithelial markers were consistent with the microarray data.
Conclusion: These results indicate that these transcriptional changes likely reflect the clinically seen more aggressive phenotype in AIP positive patients. In pituitary tumorigenesis EMT likely occurs within a specific genetic context and may be related to their increased local invasion and more aggressive behaviour. Therefore, different pathways in pituitary adenoma progression exist.
27 Apr - 01 May 2013
European Society of Endocrinology