Endocrine Abstracts

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 20–30% 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.