PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases.

Abstract

OBJECTIVE:

Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA(L206R) mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.

DESIGN, PATIENTS, AND METHODS:

In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.

RESULTS:

Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA(L206R) mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.

CONCLUSIONS:

PRKACA(L206R) is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

• Authors: Anne Thiel, Anna-Carinna Reis, Matthias Haase, Gerald Goh, Matthias Schott, Holger S Willenberg, Ute I Scholl
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 172 Issue 6 Pg. 677-85 (Jun 2015) ISSN: 1479-683X [Electronic] England
• PMID: 25750087 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 European Society of Endocrinology.

Chemical References

• CTNNB1 protein, human
• beta Catenin
• Aldosterone
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
• PRKACA protein, human
• Hydrocortisone

Topics

• Adrenal Cortex Neoplasms (genetics)
• Adrenal Hyperplasia, Congenital (genetics)
• Adrenalectomy
• Adrenocortical Adenoma (genetics)
• Adult
• Age Factors
• Aged
• Aldosterone (metabolism)
• Cushing Syndrome (genetics, surgery)
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits (genetics)
• Female
• Humans
• Hydrocortisone (metabolism)
• Male
• Middle Aged
• Mutation (genetics)
• Phenotype
• beta Catenin (genetics)