Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.

TitleRecurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.
Publication TypeJournal Article
Year of Publication2014
AuthorsGoh, G, Scholl, UI, Healy, JM, Choi, M, Prasad, ML, Nelson-Williams, C, Kunstman, JW, Kuntsman, JW, Korah, R, Suttorp, A-C, Dietrich, D, Haase, M, Willenberg, HS, Stålberg, P, Hellman, P, Akerström, G, Björklund, P, Carling, T, Lifton, RP
JournalNat Genet
Date Published2014 Jun
KeywordsAdolescent, Adrenal Gland Neoplasms, Adult, Aged, Amino Acid Sequence, Base Sequence, cdc42 GTP-Binding Protein, Cell Proliferation, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Exome, Female, Gene Deletion, Gene Dosage, HEK293 Cells, Humans, Hydrocortisone, Male, Middle Aged, Molecular Sequence Data, Mutation, Phosphorylation, Sequence Analysis, DNA, Sequence Homology, Amino Acid

Adrenal tumors autonomously producing cortisol cause Cushing's syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

Alternate JournalNat. Genet.
PubMed ID24747643
PubMed Central IDPMC4074779
Grant List / / Howard Hughes Medical Institute / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
UL1 TR000142 / TR / NCATS NIH HHS / United States
5U54HG006504 / HG / NHGRI NIH HHS / United States