Serum inhibin pro-αC is a tumor marker for adrenocortical carcinomas

Abstract

Objective: The insufficient diagnostic accuracy for differentiation between benign and malignant adrenocortical disease and lack of sensitive markers reflecting tumor load emphasize the need for novel biomarkers for diagnosis and follow-up of adrenocortical carcinoma (ACC). Design: Since the inhibin a-subunit is expressed within the adrenal cortex, the role of serum inhibin pro-aC as a tumor marker for ACC was studied in patients. Methods: Regulation of adrenal pro-aC secretion was investigated by adrenocortical function tests. Serum inhibin pro-aC levels were measured in controls (nZ181) and patients with adrenocortical hyperplasia (nZ45), adrenocortical adenoma (ADA, nZ32), ACC (nZ32), or non-cortical tumors (nZ12). Steroid hormone, ACTH, and inhibin A and B levels were also estimated in patient subsets. Results: Serum inhibin pro-aC levels increased by 16% after stimulation with ACTH (PZ0.043). ACC patients had higher serum inhibin pro-aC levels than controls (medians 733 vs 307 ng/l, P!0.0001) and patients with adrenocortical hyperplasia, ADA, or non-adrenocortical adrenal tumors (148, 208, and 131 ng/l, respectively, PZ0.0003). Inhibin pro-aC measurement in ACC patients had a sensitivity of 59% and specificity of 84% for differentiation from ADA patients. Receiver operating characteristic analysis displayed areas under the curve of 0.87 for ACC vs controls and 0.81 for ACC vs ADA (P!0.0001). Surgery or mitotane therapy was followed by a decrease of inhibin pro-aC levels in 10/10 ACC patients tested during follow-up (PZ0.0065). Conclusions: Inhibin pro-aC is produced by the adrenal gland. Differentiation between ADA and ACC by serum inhibin pro-aC is limited, but its levels may constitute a novel tumor marker for ACC.

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression

“…Primary cultures of adrenocortical cells secreted activin A, inhibin B, and inhibin pro-␣C, whereas inhibin A levels were undetectable. Adrenocortical production of inhibin pro-␣C and to a lesser extent inhibin B is compatible with the reports that these peptides can be elevated in serum of patients with adrenocortical tumors (16,22). The finding that activin A and inhibin pro-␣C were amply produced without concomitant secretion of inhibin A indicates the different cell types in which these subunits are expressed, e.g., zona glomerulosa for the inhibin ␤A-subunit and reticularis for the ␣-subunit (26,33).…”

“…The role of its antagonist inhibin in adrenocortical physiology is even more obscure, since it has failed to show consistent effects on steroidogenesis (33,36,39). On the other hand, the inhibin ␣-subunit has been implicated in adrenocortical tumor formation in murine models (14,24) and can function as a tumor marker in patients (16).…”

Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation

“…In contrast, in vivo studies have revealed increased levels of the inhibin α-subunit in serum of patients with ACC [21], [31], [32]. These findings are likely to be a consequence of the wide variation in tumor INHA expression levels, in the current study over a 1000-fold.…”

“…Furthermore, comparative genomic hybridization analyses of human ACCs described sporadic chromosomal loss of the INHA region at 2q33-36, with a predominance in childhood tumors [33], [34], [35]. On the other hand, the inhibin α-subunit was previously shown to be overexpressed in pediatric ACCs [21].…”

Melanocortin 2 Receptor-Associated Protein (MRAP) and MRAP2 in Human Adrenocortical Tissues: Regulation of Expression and Association with ACTH Responsiveness

“…The proteins of the first three genes are key steroidogenic enzymes of cortisol production, whereas the inhibin ␣-subunit is presumably involved in adrenocortical cell proliferation and can serve as a tumor marker for ACC (30,31). We measured the induction of the above-mentioned genes by ACTH in a variety of adrenocortical primary cultures as an indicator of ACTH responsiveness.…”