Thiel Anne, Reis Anna-Carinna, Haase Matthias, Goh Gerald, Schott Matthias, Willenberg Holger S, Scholl Ute I
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 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.
Eur J Endocrinol. 2015 Jun;172(6):677-85. doi: 10.1530/EJE-14-1113. Epub 2015 Mar 6.
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.
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.
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.
肾上腺腺瘤或增生导致的皮质醇增多可引起库欣综合征。近期的基因研究已确定体细胞PRKACA（L206R）突变是产生皮质醇腺瘤的病因。我们旨在比较PRKACA突变性病变与CTNNB1突变性病变的临床特征，并在单侧增生或共分泌醛固酮的肿瘤中寻找相似突变。
设计、患者与方法：本研究评估了1992年至2013年间在我院接受肾上腺切除术的60例皮质醇增多患者，并通过桑格测序法确定体细胞突变。共有36例患者患有明显的库欣综合征，其余为亚临床患者：59例为腺瘤（3例双侧），1例为增生。4个肿瘤已证实共分泌醛固酮。
在无共分泌证据的分泌皮质醇的单侧病变（n = 52）中，我们发现23.1%存在PRKACA（L206R）体细胞突变，23.1%存在CTNNB1（S45P、S45F）突变，5.8%存在GNAS（R201C）突变，1.9%存在CTNNB1 + GNAS（S45P、R201H）突变。PRKACA和GNAS突变相互排斥。在共分泌肿瘤中，2个（50%）存在KCNJ5（G151R和L168R）突变。增生腺体显示PRKACA（L206R）突变，而双侧腺瘤患者未发现已知的体细胞突变。与非PRKACA突变或CTNNB1突变性病变相比，PRKACA突变性病变与更年轻的年龄、明显的库欣综合征以及更高的皮质醇水平相关。CTNNB1突变与右侧病变的相关性比左侧病变更显著。
PRKACA（L206R）不仅存在于腺瘤中，也存在于单侧增生中，且与更严重的自主性皮质醇分泌相关。双侧腺瘤可能由未知的种系突变引起。
