Novel Somatic Mutations in the Catalytic Subunit of the Protein Kinase A as a Cause of Adrenal Cushing's Syndrome: A European Multicentric Study
Novel Somatic Mutations in the Catalytic Subunit of the Protein Kinase A as a Cause of Adrenal Cushing's Syndrome: A European Multicentric Study
复制标题
DOI：
10.1210/jc.2014-2152
复制
发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Reincke, Martin
中科院分区：
文献类型：
--
作者：
Di Dalmazi, Guido;Kisker, Caroline;Reincke, Martin
背景：最近在大部分与库欣综合征相关的散发性腺瘤中发现了编码蛋白激酶 A (PKA) 催化亚基的 PRKACA 基因的体细胞突变。目的是分析一大群肾上腺皮质肿块患者的 PRKACA 突变。方法：纳入来自 9 个欧洲中心的样本（德国，n = 4；意大利，n = 4；法国，n = 1）。样本取自 149 名患者，这些患者患有非分泌性腺瘤（n = 32 + 2 例瘤周）、亚临床皮质醇增多症（n = 36）、库欣综合征（n = 64 + 2 例瘤周）、产生雄激素的肿瘤（n = 4）、肾上腺皮质癌（n = 5 + 2 例瘤周）和原发性双侧大结节肾上腺增生（n = 8）。血液样本来自患有非分泌性腺瘤 (n = 15)、亚临床皮质醇增多症 (n = 10) 和库欣综合征 (n = 35) 的患者。收集临床和激素数据。对PRKACA基因的外显子6和7进行PCR扩增并直接测序。结果：22/64的库欣综合征患者样本（34%）中发现PRKACA杂合突变。在瘤周组织和血液样本或其他检查的肿瘤中没有发现突变。 c.617A>C (p. Leu206Arg) 发生在 18/22 名患者中。此外，还发现了两种新突变：三名患者中的 c.600_601insGTG/p.Cys200_Gly201insVal 和一名患者中的 c.639C>G + c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg)。所有突变都涉及与 PKA 调节亚基和催化亚基之间相互作用有关的区域。与非突变受试者相比，患有体细胞 PRKACA 突变的患者在地塞米松测试后表现出更高水平的皮质醇，并且腺瘤尺寸更小。结论：这些数据证实并扩展了之前的观察结果，即体细胞 PRKACA 突变对引起库欣综合征的肾上腺皮质腺瘤具有特异性。
Context: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses.Methods: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed.Results: PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p. Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G + c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects.Conclusions: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.