Abstract
The association of pathological features of cortisol-producing adrenocortical adenomas (ACAs) with somatic driver mutations and their molecular classification remain unclear. In this study, we explored the association between steroidogenic acute regulatory protein (StAR) expression and the driver mutations activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling to identify the pathological markers of ACAs. Immunohistochemical staining for StAR and mutations in the protein kinase cAMP-activated catalytic subunit alpha (PRKACA), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) and guanine nucleotide binding protein, alpha stimulating (GNAS) genes were examined in 97 ACAs. The association of StAR expression with the clinical and mutational features of the ACAs was analyzed. ACAs with mutations in PRKACA, GNAS, and PRKAR1A showed strong immunopositive staining for StAR. The concordance between high StAR expression and mutations activating cAMP/PKA signaling in the ACAs was 99.0%. ACAs with high expression of StAR had significantly smaller tumor volume (P < 0.001) and higher urinary cortisol per tumor volume (P = 0.032) than those with low expression of StAR. Our findings suggest that immunohistochemical staining for StAR is a reliable pathological approach for the diagnosis and classification of ACAs with cAMP/PKA signaling-activating mutations.
Highlights
Cortisol-producing adrenocortical adenomas (ACAs) are the main cause of adrenal Cushing’s syndrome, which leads to a variety of metabolic abnormalities including central obesity, diabetes, hypertension, myopathy, and osteoporosis [1,2]
The cytoplasmic steroidogenic acute regulatory protein (StAR) immunostaining was more intense in tissues with mutations in protein kinase cAMP-activated catalytic subunit alpha (PRKACA), GNAS, and PRKAR1A compared to the wild-type tumors (Fig 1), whereas StAR was not differentially expressed among the tissue samples with mutations in PRKACA, GNAS, and PRKAR1A
These indicate that high expression of StAR occurred in the mutated ACAs, and two distinct groups of tumors could be identified based on the differential expression of StAR
Summary
We aimed to explore the association of StAR expression with the mutated genes in cAMP/PKA signaling and functional characteristics of the ACAs
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