ECE2015 Oral Communications Adrenal 2 (5 abstracts)
The Notch ligand Jagged1 is up-regulated in adrenocortical carcinomas and is associated with a favourable clinical outcome
Cristina Ronchi 1 , Silviu Sbiera 1 , Barbara Altieri 1 , Sonja Steinhauer 1 , Vanessa Wild 2 , Michaela Bekteshi 1 , Matthias Kroiss 1 , Martin Fassnacht 1 & Bruno Allolio 1
1Endocrine and Diabetes Unit, University Hospital Wuerzburg, Wuerzburg, Germany; 2Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
Background: Adrenocortical tumours consist of frequent adrenocortical adenomas (ACA) and highly malignant (ACC) with a still incompletely understood pathogenesis. Dysregulation of Notch signalling pathway is implicated in several cancers with oncogenic or tumour suppressor functions. Copy number gains and over-expression of Jagged1, a ligand of Notch receptor, was reported in ACC. The aim of the study was to evaluate the expression of Jagged1 and other Notch-related factors in adrenocortical tumors and to correlate it with clinical outcome.
Material and methods: mRNA expression of JAG1, NOTCH1, CTNNB1, and selected target genes of Notch signalling (HES1, HES5 and HEY2) and Wnt/β-catenin pathway (LEF1) was evaluated in 80 fresh frozen samples (28 normal adrenal glands=NAG, 24 ACA, 28 ACC) by quantitative real-time PCR. Immunohistochemistry was performed in 221 tissues on paraffin slides (16 NAG, 27 ACA, 178 ACC) for Jagged1, activated Notch1 (aNotch1) and HEY2 staining. The relationship with nuclear β-catenin expression was also investigated.
Results: mRNA expression of JAG1, NOTCH1, CTNNB1, and target genes was not significantly different between normal and neoplastic adrenal glands. At protein level, all factors evaluated were highly expressed (H-score 2–3) in a larger proportion of ACCs than in ACAs and NAG (Jagged1 in 27, 15 and 10% of NA, respectively, P=0.0004; aNotch1 in 13%, 8% and none of NAG, P<0.0001; HEY2 in 66, 61 and 33%, P=0.0001). High Jagged1 expression was associated with earlier ENSAT tumour stages (P=0.07) and lower number of metastases (P=0.08) in ACC. Accordingly, high Jagged1 levels impacted favourably on overall survival (n=168, 131 vs 30 months, P=0.0023, HR=0.45) and progression free survival (37 vs 9 months, P=0.0023, HR=0.51), even after adjustment for ENSAT tumour stage (P=0.005) and nuclear β-catenin expression (P=0.009).
Conclusion: Jagged1 is overexpressed in a subgroup of ACCs, being associated with a more differentiated phenotype and better clinical outcome. Notch1 signaling pathway activation might be involved in adrenocortical tumor progression, but still needs to be better investigated.
Disclosure: This work was supported by the Wilhelm Sander Foundation (grant number 2012.095.1).
Volume 37
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Endocrine Abstracts
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