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Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Zhou J 1 , Azizan EAB 2 , Cabrera CP 3 , Fernandes-Rosa FL 4 , Boulkroun S 4 , Argentesi G 1 Show all authors , Cottrell E 5 , Amar L 4 , Wu X 1 , O'Toole S 1 , Goodchild E 1 , Marker A 6 , Senanayake R 7 , Garg S 1 , Åkerström T 8 , Backman S 8 , Jordan S 9 , Polubothu S 10 , Berney DM 11 , Gluck A 12 , Lines KE 12 , Thakker RV 12 , Tuthill A 13 , Joyce C 14 , Kaski JP 15 , Karet Frankl FE 16 , Metherell LA 5 , Teo AED 17 , Gurnell M 7 , Parvanta L 18 , Drake WM 19 , Wozniak E 20 , Klinzing D 21 , Kuan JL 21 , Tiang Z 21 , Gomez Sanchez CE 22 , Hellman P 8 , Foo RSY 21 , Mein CA 20 , Kinsler VA 9 , Björklund P 8 , Storr HL 5 , Zennaro MC 23 , Brown MJ 24

Affiliations 

  • 1 Endocrine Hypertension, Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK
  • 2 Endocrine Hypertension, Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK. elena.azizan@ukm.edu.my
  • 3 NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • 4 Université de Paris, PARCC, Inserm, Paris, France
  • 5 Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
  • 6 Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK
  • 7 Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
  • 8 Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
  • 9 Cellular Pathology Department, Royal London Hospital, London, UK
  • 10 Genetics and Genomic Medicine, University College London Great Ormond Street Institute of Child Health, London, UK
  • 11 Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
  • 12 Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  • 13 Department of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland
  • 14 Clinical Biochemistry, Cork University Hospital, Cork, Ireland
  • 15 Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital and University College London Institute of Cardiovascular Science, London, UK
  • 16 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  • 17 Dept of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  • 18 Department of Surgery, St Bartholomew's Hospital, London, UK
  • 19 Department of Endocrinology, St Bartholomew's Hospital, London, UK
  • 20 Barts and London Genome Centre, School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK
  • 21 Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  • 22 G.V. (Sonny) Montgomery VA Medical Center and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
  • 23 Université de Paris, PARCC, Inserm, Paris, France. maria-christina.zennaro@inserm.fr
  • 24 Endocrine Hypertension, Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK. morris.brown@qmul.ac.uk
Nat Genet, 2021 Sep;53(9):1360-1372.
PMID: 34385710 DOI: 10.1038/s41588-021-00906-y

Abstract

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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