Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Science. 2014 May 23;344(6186):913-7. doi: 10.1126/science.1249480. Epub 2014 Apr 3.
Adrenal Cushing's syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), adrenocorticotropic hormone-independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing's syndrome.
肾上腺库欣综合征是由肾上腺皮质肿瘤和增生导致的糖皮质激素过度产生引起的，会导致代谢紊乱。我们对 49 对血-肿瘤样本进行了全外显子组测序，并对 44 个产生皮质醇的肾上腺皮质腺瘤（ACAs）、促肾上腺皮质激素非依赖性大结节性肾上腺皮质增生（AIMAHs）和肾上腺皮质嗜酸细胞瘤（ADOs）进行了 RNA 测序。我们在 69.2%（39 个中的 27 个）的 ACAs 中发现了 PRKACA 基因中的一个热点，该基因具有 L205R 突变，并在总共 87 个 ACAs 中的 65.5%得到了验证。我们的数据表明，位于蛋白激酶 A（PKA）催化亚基 P+1 环的激活 L205R 突变促进了 PKA 底物磷酸化和靶基因表达。此外，我们在 AIMAHs 中发现了复发性突变基因 DOT1L，在 ADOs 中发现了 CLASP2。总之，这些数据突出了肾上腺库欣综合征中潜在的功能性突变基因。
