title: Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.
abstract: 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.
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. [3] Division of Nephrology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ute I
authors.initials: UI
authors.lastname: Scholl
authors.affiliation: Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Healy
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. [3] Yale Center for Mendelian Genomics, New Haven, Connecticut, USA.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kunstman
authors.affiliation: Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kuntsman
authors.affiliation: Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Department of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Anna-Carinna
authors.initials: AC
authors.lastname: Suttorp
authors.affiliation: Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Haase
authors.affiliation: Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Holger S
authors.initials: HS
authors.lastname: Willenberg
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stålberg
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Akerström
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
authors.affiliation: 1] Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. [3] Yale Center for Mendelian Genomics, New Haven, Connecticut, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D049109:Cell Proliferation; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D057809:HEK293 Cells; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D020764:cdc42 GTP-Binding Protein / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human; D020764:cdc42 GTP-Binding Protein; D006854:Hydrocortisone
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