PD3-06 IMPACT OF PRIMARY HISTOLOGY ON DISEASE FREE SURVIVAL AFTER MINIMALLY INVASIVE ADRENALECTOMY FOR METASTATIC CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Cushing’s syndrome is characterized by excess cortisol production from adrenocortical grand and presents various symptoms and signs. In corticotropin-independent Cushing’s syndrome, the excess cortisol production is attributed to an adrenocortical adenoma in the majority of cases, in which the underlying molecular pathogenesis has been poorly understood. METHODS: Somatic mutations in 8 adrenocortical tumors associated with corticotropin-independent Cushing’s syndrome was explored by whole exome sequencing, followed by target Sanger sequencing in an additional 57 cases. Functional impacts of detected mutations were also investigated by in vitro binding assays and assays for kinase activity. RESULTS: We identified novel hotspot mutation in PRKACA which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (PKA). PRKACA mutations were found in 34 (52.3%) of 65 patients and invariably resulted in L206R variant protein. We also detected activating mutations of G-protein subunit as (GNAS) (R201C and R201H) in an additional 11 (16.9%) patients, which lead to constitutive accumulation of cAMP. Mutations in PRKACA and GNAS were completely mutually exclusive and accounted for 70% of samples had mutations in genes involved in the cAMP/PKA signaling pathway. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA which inhibits catalytic activity of PKA and lead to constitutive, cAMP independent PKA activation. CONCLUSIONS: Corticotropin-independent Cushing’s syndrome is frequently associated with somatic mutations in PRKACA or GNAS. The current results highlight the major role of constitutive activation of the cAMP/PKA signaling pathway by somatic mutations in Corticotropin-independent Cushing’s syndrome and provide novel insight into the diagnosis and treatment of this unique syndrome.