Endocrine Abstracts

Background: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) gene have been implicated in the tumorigenesis of patients with familial isolated pituitary adenoma (FIPA). Around 25% of FIPA patients have an identified AIP mutation; in the remainder of FIPA patients, molecular mechanisms involved in pituitary tumorigenesis have yet to be elucidated.

Aims: To identify the genes and molecular mechanisms involved in the pituitary tumorigenesis of AIP mutation negative FIPA patients (AIPmut negative),

Methods: Gene expression analysis of FIPA AIPmut negative (AIPmut negative, n=5), FIPA AIPmut positive (AIPmut positive, n=4), normal pituitary (NP, n=5), sporadic somatotrophinoma (Acro, n=3) and non-functioning pituitary adenoma (NFPA, n=4) tumour samples were carried out using the Affymetrix Gene-Chip HG-U133 plus 2.0 array. Five significantly differentially expressed genes were selected for validation using RT-qPCR with standard curve method data analysis. Independent AIPmut negative (n=1), Acro (n=5), NFPA (n=4) and NP (n=3) samples were also validated.

Results: Among differentially expressed genes in AIPmut negative tumours compared to NP, Src Kinase Associated Phosphoprotein 2 (SKAP2) was identified as upregulated, which has been implicated in tumour metastasis and in the inhibition of actin polymerisation. SKAP2 was overexpressed in AIPmut negative tumours staining positive for growth hormone (AIPneg-Acro, n=3) compared to NP (n=6; 3.09±0.82 vs 1.00±0.10). SKAP2 is expressed similarly in Acro (n=9) compared to NP (1.33±0.30 vs 1.00±0.10) and underexpressed in NFPA (n=9) and non-functioning familial AIPmut negative tumours (n=2) versus NP (0.16±0.30 vs 1.00±0.10; 0.37±0.03 vs 1.00±0.10).

Conclusions: SKAP2 is overexpressed in AIPneg-Acro compared to NP, NFPA and familial AIPneg NFPA. SKAP2 plays a role in tumour metastasis and may explain the tendency of these tumours to invade locally only. SKAP2 is therefore a novel candidate in pituitary tumorigenesis and target for protein expression and functional studies.