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


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.
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Anne
A
Thiel
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Anna-Carinna
AC
Reis
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Matthias
M
Haase
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Gerald
G
Goh
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Matthias
M
Schott
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany.
Holger S
HS
Willenberg
Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany ute.scholl@med.uni-duesseldorf.de.
Ute I
UI
Scholl
D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000315:Adrenalectomy; D018246:Adrenocortical Adenoma / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000450:Aldosterone / Q000378:metabolism*; D003480:Cushing Syndrome / Q000235:genetics* / Q000601:surgery; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D051176:beta Catenin / Q000235:genetics*
C495270:CTNNB1 protein, human; D051176:beta Catenin; D000450:Aldosterone; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human; D006854:Hydrocortisone