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Nat Genet. 2014 Jun;46(6):613-7. doi: 10.1038/ng.2956. Epub 2014 Apr 20.

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

Author information

1
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.
2
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.
3
Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA.
4
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.
5
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
6
Department of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany.
7
Institute of Pathology, University of Bonn, Bonn, Germany.
8
Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
9
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
10
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.

Erratum in

  • Nat Genet. 2014 Jul;46(7):759. Kuntsman, John W [corrected to Kunstman, John W].

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.

PMID:
24747643
PMCID:
PMC4074779
DOI:
10.1038/ng.2956
[Indexed for MEDLINE]
Free PMC Article

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