Agouti-related peptide: a promising prognostic biomarker in adrenocortical carcinoma. Results from a large single-centre cross-sectional analysis

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a heterogeneous prognosis. To date, there are no reliable circulating biomarker to predict clinical outcomes in ACC. Agouti-related peptide (AgRP), an orexigenic hypothalamic neuropeptide, is also produced by the adrenal gland. However, its expression in adrenal tumours remains unexplored. OBJECTIVE: To evaluate AgRP levels in tissue and plasma of patients with ACC, benign adrenal tumours (BAT), and other malignancies. METHODS: AgRP mRNA expression was assessed in silico, and protein levels were analysed by immunohistochemistry in ACC and BAT. Plasma AgRP (pAgRP) was measured using ELISA in patients with ACC, BAT, and other cancers. Tumour burden of ACC was quantified using RECIST1.1. RESULTS: AgRP mRNA levels were higher in ACC than in BAT (3.0 vs 2.4, P < .0001). AgRP tissue expression was higher in ACC compared to BAT (H-score 120 [49] vs 80 [48], P < .0001). pAgRP was more elevated in ACC than BAT and other malignancies (1.3 vs 0.3 vs 0.2 ng/mL, all P < .0001) and was higher in ACC with high tumour burden than those with low and those ACC-free after surgery (2.7 vs 0.6 vs 0.3 ng/mL, P < .0001). pAgRP increased with the number of metastatic sites (≥4 sites: 2.7 ng/mL vs 2-3: 1.5 ng/mL vs 1: 0.5 ng/mL, P < .05). In multivariable Cox regression, elevated pAgRP was independently associated with worse progression-free (HR = 2.654) and overall survival (HR = 2.624) (both P < .05). CONCLUSIONS: AgRP is more highly expressed in both tissue and plasma of ACC compared to BAT and other cancers. Its strong association with tumour burden and prognosis highlights its potential as biomarker in ACC.