SFEBES2021 Oral Communications Adrenal and Cardiovascular (6 abstracts)
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 adrenals could suggest the existence of co-driver mutations which influence the development or phenotype of APAs . Gain-of-function mutations in both CTNNB1 and the G-protein coupled receptor GNA11 were found by whole exome sequencing in 3/10 APAs. Further sequencing of known CTNNB1-mutant APAs from UK/Irish patients led to 10/10 with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11/Q. Nine out of ten patients presented at times of high LH/HCG (puberty, pregnancy, menopause). Their double-mutant APAs had >10-fold higher expression of multiple transcripts, including LHCGR, than other APAs. Transfections of NCI-H295R cells (an immortalised adrenocortical cell line with S45P mutation of CTNNB1) with GNA11 Q209H, L or P increased aldosterone secretion and CYP11B2 expression (encoding aldosterone synthase) by 2.5-6.1-fold and 8.0-9.8-fold (P = <0.0005) respectively, compared to vector-transfected cells. H295R cells, and one double-mutant APA, did not express LHCGR, and pointed to alternative mediators of the double-mutant phenotype, e.g. TMEM132E. Fresh adrenal adenoma cells harvested post adrenalectomy were transfected with CTNNB1 and GNA11 mutants, alone or together, and compared with cells transfected with vector or wild-type genes. Aldosterone secretion, CYP11B2 expression and LHCGR were increased substantially more by the combination than by single mutant, or wild-type transfections (P = <0.0001). LHCGR expression was also assessed via immunofluorescence, which showed cells harbouring both mutations to stain the most intensely. In conclusion, somatic mutations of the Q209 residue of GNA11/Q appear always to co-exist with exon 3 mutations of CTNNB1 and to cause a unique clinical and APA phenotype. These experiments are part of a larger study, which also compared APAs with single- or double-mutation of CTNNB1, from French and Swedish cohorts .
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2. Zhou et al. Nat Gen in press.
08 Nov 2021 - 10 Nov 2021