ACTH-Independent Multinodular Adrenal Hyperplasia with Dominant Nodule: Expression Profile Support a Neoplastic-Like and Non-Functional Presentation
Emma Garratt, Alfredo Blanes, Salvador J Diaz-Cano. Barts and The London Hospitals, London, United Kingdom; University of Malaga School of Medicine, Malaga, Spain; King's College Hospital, London, United Kingdom
Background: ACTH-independent multinodular adrenal hyperplasia is a heterogeneous disease, some of them presenting with dominant nodules that can be difficult to differentiate from adrenal adenomas. We investigate the contributions of Jak-Stat pathways and cell growth-proliferation pathways in this process.
Design: We selected ACTH-independent nodular hyperplasias with (12, AIMAH) and without (23, ACNH) dominant nodule (3:1 size ratio with second biggest), adrenocortical adenomas (ACA, 74), and carcinomas (ACC, 22) (WHO criteria) to analyze PI3 Kinase/AKT pathway (AKT1, BCL2, CCND1, FN1, JUN, MMP7, MYC), CREB pathway (CYP19A1, EGR1, FOS), Jak-Stat pathway (CXCL9, IL4, IL4R, IRF1, MMP10, NOS2A), and cell growth-proliferation (MKI67, TERT, CAV2, EGFR, ERBB3, FGFBP1, IGF2, IGFBP4, MST1R, PDGFRB, TGFB1, TGFB2, TGFB3) in a low-density selective cDNA array. Total RNA was extracted, cleaned from normal and neoplastic tissues (RNeasy columns), first-strand cDNA synthesized using T7-(dT24)-oligomer and used as template for cRNA synthesis. The cRNA was fragmented, Cy3-/Cy5-labeled, and hybridized to arrays noncompetitively, cross-validating the results (expression factor>2, significance<0.01). Variables were studied regarding histological diagnosis and presence of dominant nodule. Significant variables were then tested on tissue sections by in-situ techniques.
Results: AIMAH revealed significant downregulation of CCND1, FN1, CYP19A1, CXCL9, IL4, ERBB3, and MST1R; and upregulation of AKT1, JUN, CAV2, and TGFB2. All these markers segregated differently in the comparison AIMAH vs. ACC. The differential markers with benign lesions were: TERT, CCND1, and TGFB2 with ACNH; JUN, and CYP19A1 with ACA. Remaining genes showed no significant differences.
Conclusions: AIMAH expression profile reveals a non-inflammatory (downregulation of key markers of Jak-Stat pathway), and antiapoptotic (AKT1 and TFGB2 pathways) background that contribute to longer cell survival (TERT upregulation) and neoplastic-like expansion. Down-regulaton of JUN and CYP19A1 would contribute to a lower cellular functionality and a clinical presentation with mass effect.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 47, Tuesday Afternoon