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Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

¹ INSERM U567, CNRS UMR8104, Endocrinology, Metabolism and Cancer Department, Institut Cochin, 75014 Paris, France² Université Paris Descartes,, 75014 Paris, France³ Assistance Publique Hôpitaux de Paris,, Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France⁴ Assistance Publique Hôpitaux de Paris,, Department of Pathology, Hôpital Cochin, Paris, France and ⁵ COMETE-INCA-Rare Adrenal Cancer Network,, 75014 Paris, France

(Correspondence should be addressed to J Bertherat who is now at Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Email: jerome.bertherat{at}cch.aphp.fr)

Objective: The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics.

Methods: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured.

Results: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%±4 vs 100%±19, P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37±0.31 vs 1.00±0.20, P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors.

Conclusion: This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.