Low SGK1 Expression in Human Adrenocortical Tumors Is Associated with ACTH-Independent Glucocorticoid Secretion and Poor Prognosis

CONTEXT: Using single-nucleotide polymorphism analysis, we observed allelic loss of the gene for serum glucocorticoid (GC) kinase 1 (SGK1), a GC-responsive kinase involved in multiple cellular functions, in a subset of cortisol-secreting adenomas. OBJECTIVE: Our objective was to analyze SGK1 expression in adrenocortical tumors and to further characterize its role in ACTH-independent cortisol secretion, tumor progression, and prognosis. DESIGN AND SETTING: Gene expression levels of SGK1, SGK3, and CTNNB1 (coding for β-catenin) and protein expression levels of SGK1, nuclear β-catenin, and phosphorylated AKT were determined in adrenocortical tumors and normal adrenal glands. PATIENTS: A total of 227 adrenocortical tumors (40 adenomas and 187 carcinomas) and 25 normal adrenal tissues were included. Among them, 62 frozen tumor samples were used for mRNA analysis and 203 tumors were investigated on tissue microarrays or full standard slides by immunohistochemistry. MAIN OUTCOME MEASURES: We evaluated the relationship between SGK1 mRNA and/or protein levels and clinical parameters. RESULTS: SGK1 mRNA levels were lower in cortisol-secreting than in nonsecreting tumors (P < 0.005). Nonsecreting neoplasias showed a significant correlation between SGK1 and CTNNB1 mRNA levels (P < 0.001; r = 0.57). Low SGK1 protein levels, but not nuclear β-catenin and phosphorylated AKT, were associated with poor overall survival in patients with adrenocortical carcinoma (P < 0.005; hazard ratio = 2.0; 95% confidence interval = 1.24–3.24), independent of tumor stage and GC secretion. CONCLUSION: Low SGK1 expression is related to ACTH-independent cortisol secretion in adrenocortical tumors and is a new prognostic factor in adrenocortical carcinoma.