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.
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.


CONCLUSIONS
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.
Vincent-Dejean
C
C
INSERM U567, CNRS UMR8104, Endocrinology, Metabolism and Cancer Department, Institut Cochin, 75014 Paris, France.
Cazabat
L
L
Groussin
L
L
Perlemoine
K
K
Fumey
G
G
Tissier
F
F
Bertagna
X
X
Bertherat
J
J
D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; C517837:PRKAR2B protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006854:Hydrocortisone