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.
Authors: Junhua Zhou,1,2,27 Elena A. B. Azizan,1,3,27 Claudia P. Cabrera,2,4,27 Fabio L. Fernandes-Rosa,5,27 Sheerazed Boulkroun,5,27 Giulia Argentesi,1,2 Emily Cottrell,6 Laurence Amar,5,7 Xilin Wu,1,2 Sam O’Toole,1,2 Emily Goodchild,1,2 Alison Marker,8 Russell Senanayake,9 Sumedha Garg,1,2,9 Tobias Åkerström,10 Samuel Backman,10 Suzanne Jordan,11 Satyamaanasa Polubothu,12 Daniel M. Berney,13 Anna Gluck,14 Kate E. Lines,14 Rajesh V. Thakker, Antoinette Tuthill, Caroline Joyce, Juan Pablo Kaski, Fiona E. Karet Frankl, Lou A. Metherell, Ada E. D. Teo, Mark Gurnell, Laila Parvanta, William M. Drake, Eva Wozniak, David Klinzing, Jyn Ling Kuan, Zenia Tiang, Celso E. Gomez Sanchez, Per Hellman, Roger S. Y. Foo, Charles A. Mein, Veronica A. Kinsler, Peyman Björklund, Helen L. Storr, Maria-Christina Zennaro, Morris J. Brown
Keywords: somatic mutation, GNA11, GNAQ, puberty, pregnancy, menopause
DOI Number: 10.1038/s41588-021-00906-y Publication Year: 2021
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