Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome

Yanan Cao, Minghui He, Zhibo Gao, Ying Peng, Yanli Li, Lin Li, Weiwei Zhou, Xiangchun Li, Xu Zhong, Yiming Lei, Tingwei Su, Hang Wang, Yiran Jiang, Lin Yang, Wei Wei, Xu Yang, Xiuli Jiang, Li Liu, Juan He, Junna Ye, Qing Wei, Yingrui Li, Weiqing Wang, Jun Wang, Guang Ning

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.