Endocrine Abstracts

Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) predispose to pituitary adenomas in young patients, often presenting as familial isolated pituitary adenoma (FIPA) kindreds. Pituitary adenomas in patients with AIP mutations (AIPmut) are usually somatotropinomas, which are more aggressive and have poorer responses to somatostatin analogues than their non-mutated counterparts. Given the rarity of this condition, the molecular pathogenesis of the AIP mutated tumors is still incomplete.

The aim of this study was to determine the microRNA (miRNA) expression profile of AIP mutation-positive somatotropinomas. Tumours from patients carrying AIP mutations (AIPmut; seven tumors from six patients) were compared with somatotropinomas from mutation-negative individuals (AIPwt). RNA was extracted from formalin-fixed, paraffin-embedded tissues. For miRNA profiling, the GeneChip miRNA 1.0 arrays from Affymetrix were used. After filtering for detection and applying the Benjamini-Hochberg correction of data, a cut-off P-value of <0.05 was chosen. This resulted in a total of nine non-coding RNAs significantly differentially expressed between AIPmut and AIPwt adenomas by a fold change > 1.5. Six were up-regulated and three down-regulated in AIPmut versus AIPwt tumors. Based on Ingenuity Pathway Analysis, these miRNAs are involved in cell proliferation and motility, cell death and cell cycle. We validated the expression of 5 differentially regulated miRNAs using individual Taqman RT-PCR assays, which allowed us to discount one miRNA. The functions of the differentially regulated miRNAs were assessed in in vitro studies, in addition to the role of mutant AIP proteins in regulating miRNAs expression. The identification of biologically relevant miRNAs regulated by AIPmut may give insights into the molecular pathogenesis of AIP-associated somatotropinomas.

Disclosure: This work was supported by Pfizer.