Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing's syndrome: a European multicentric study

G Di Dalmazi, C Kisker, D Calebiro… - The Journal of …, 2014 - academic.oup.com
G Di Dalmazi, C Kisker, D Calebiro, M Mannelli, L Canu, G Arnaldi, M Quinkler, N Rayes…
The Journal of Clinical Endocrinology & Metabolism, 2014academic.oup.com
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 …
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.
Oxford University Press