Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause
Junhua Zhou
(1)
,
Elena Azizan
(1, 2)
,
Claudia Cabrera
(1)
,
Fabio Fernandes-Rosa
(3)
,
Sheerazed Boulkroun
(3)
,
Giulia Argentesi
(1)
,
Emily Cottrell
(1)
,
Laurence Amar
(3, 4)
,
Xilin Wu
(1)
,
Sam O’toole
(1)
,
Emily Goodchild
(1)
,
Alison Marker
(5)
,
Russell Senanayake
,
Sumedha Garg
(1)
,
Tobias Åkerström
(6)
,
Samuel Backman
(6)
,
Suzanne Jordan
(7)
,
Satyamaanasa Polubothu
(8)
,
Daniel Berney
(1)
,
Anna Gluck
(9)
,
Kate Lines
(9)
,
Rajesh Thakker
(9)
,
Antoinette Tuthill
,
Caroline Joyce
,
Juan Pablo Kaski
(8)
,
Fiona Frankl
(10)
,
Lou Metherell
(1)
,
Ada Teo
(11)
,
Mark Gurnell
,
Laila Parvanta
(12)
,
William Drake
(12)
,
Eva Wozniak
(1)
,
David Klinzing
(11)
,
Jyn Ling Kuan
(11)
,
Zenia Tiang
(11, 13)
,
Celso Gomez Sanchez
(14)
,
Per Hellman
(6)
,
Roger Foo
(11)
,
Charles Mein
(1)
,
Veronica Kinsler
(7)
,
Peyman Björklund
(6)
,
Helen Storr
(1)
,
Maria-Christina Zennaro
(3, 4)
,
Morris Brown
(1)
1
QMUL -
Queen Mary University of London
2 UKM - National University of Malaysia [Bandar Baru Bangi]
3 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
4 HEGP - Hôpital Européen Georges Pompidou [APHP]
5 Addenbrooke's Hospital
6 Uppsala University
7 Royal Free Hospital [London, UK]
8 UCL - University College of London [London]
9 University of Oxford
10 CAM - University of Cambridge [UK]
11 NUS - National University of Singapore
12 St Bartholomew's Hospital (London)
13 A*STAR - Agency for science, technology and research [Singapore]
14 UMMC - University of Mississippi Medical Center
2 UKM - National University of Malaysia [Bandar Baru Bangi]
3 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
4 HEGP - Hôpital Européen Georges Pompidou [APHP]
5 Addenbrooke's Hospital
6 Uppsala University
7 Royal Free Hospital [London, UK]
8 UCL - University College of London [London]
9 University of Oxford
10 CAM - University of Cambridge [UK]
11 NUS - National University of Singapore
12 St Bartholomew's Hospital (London)
13 A*STAR - Agency for science, technology and research [Singapore]
14 UMMC - University of Mississippi Medical Center
Junhua Zhou
- Fonction : Auteur
- PersonId : 1193612
- ORCID : 0000-0002-8593-8393
Elena Azizan
- Fonction : Auteur
- PersonId : 1193613
- ORCID : 0000-0002-5549-4242
Fabio Fernandes-Rosa
- Fonction : Auteur
- PersonId : 794608
- ORCID : 0000-0002-0162-0792
Sheerazed Boulkroun
- Fonction : Auteur
- PersonId : 1183982
- ORCID : 0000-0002-8796-7534
Emily Cottrell
- Fonction : Auteur
- PersonId : 1193614
- ORCID : 0000-0001-6773-6547
Sam O’toole
- Fonction : Auteur
- PersonId : 1193615
- ORCID : 0000-0002-8943-8556
Russell Senanayake
- Fonction : Auteur
Sumedha Garg
- Fonction : Auteur
- PersonId : 1193616
- ORCID : 0000-0002-4375-8968
Rajesh Thakker
- Fonction : Auteur
- PersonId : 1193619
- ORCID : 0000-0002-1438-3220
Antoinette Tuthill
- Fonction : Auteur
- PersonId : 1193620
- ORCID : 0000-0002-1460-517X
Caroline Joyce
- Fonction : Auteur
Juan Pablo Kaski
- Fonction : Auteur
- PersonId : 1193621
- ORCID : 0000-0002-0014-9927
Lou Metherell
- Fonction : Auteur
- PersonId : 1193622
- ORCID : 0000-0002-0530-3524
Ada Teo
- Fonction : Auteur
- PersonId : 1193623
- ORCID : 0000-0002-8832-0409
Mark Gurnell
- Fonction : Auteur
- PersonId : 1193624
- ORCID : 0000-0001-5745-6832
Zenia Tiang
- Fonction : Auteur
- PersonId : 1193625
- ORCID : 0000-0003-1182-0023
Roger Foo
- Fonction : Auteur
- PersonId : 1193626
- ORCID : 0000-0002-8079-4618
Helen Storr
- Fonction : Auteur
- PersonId : 1193627
- ORCID : 0000-0002-9963-1931
Maria-Christina Zennaro
- Fonction : Auteur
- PersonId : 764446
- ORCID : 0000-0001-5449-9191
- IdRef : 105967475
Morris Brown
- Fonction : Auteur
- PersonId : 1193628
- ORCID : 0000-0001-8409-1082
Résumé
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.