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 (nZ52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1CGNAS (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.

GNAS mutations in adrenal aldosterone-producing adenomas [Rapid Communication]

“…Therefore, mutations in GNAS may induce mild hypercortisonemia in CPAs and APAs. Mutations in KCJN5 may be specific for adenomas strongly producing aldosterone, as we previously reported, while those in PRKACA may be specific for tumors showing overt Cushing's syndrome [17,23].…”

“…Furthermore, we found 2 GNAS mutations (p.R201S and p.R201C) in 15 CPAs with Cushing's syndrome, and p.R201C in 9 CPAs with subclinical Cushing's syndrome (Fig. 2) [23]. They found KCNJ5 mutations in 2 cases of 4 CPAs co-secreting aldosterone, but no mutations in either PRKACA or GNAS genes in any of them.…”

Activating PRKACB somatic mutation in cortisol-producing adenomas

“…Beyond the typical clinical picture, overt CS is associated with severe comorbidities and increased mortality (22,23). Patients whose tumors harbor PRKACA mutations present at a younger age at diagnosis, higher cortisol levels, and, interestingly, smaller-size tumors than CPAs without mutations (24,25). The present patient had as well an overt CS and a young age at diagnosis, but the size of the adenoma seems to be larger than described for PRKACA mutation (25).…”

PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas

“…Although subclinical Cushing´s syndrome has been observed in up to 21% of PA cases in some series (30), no PRKACA mutations have been identified in two recent reports (31,32). In fact, considering the current series of 122 APAs, PRKACA mutations seem to occur only in a very small fraction of PA cases.…”