Divergent surgical outcomes for CACNA1D- and KCNJ5-mutant aldosteronomas are traceable to their cell-of-origin and most differentially expressed gene, CCM2L

Only 30% of patients with unilateral primary aldosteronism were cured by adrenalectomy, with significant differences in gene expression linked to mutation types.

Summary and findings

This study investigates the differential surgical outcomes for aldosterone-producing adenomas (APAs) with KCNJ5 and CACNA1D mutations. The analysis included gene expression profiles from 28 samples, with a focus on the gene CCM2L, which was found to be 33-fold upregulated (p=10^-26). The findings suggest that the cellular origin of these mutations may influence clinical outcomes.

Abstract

<title>Abstract</title> <p>In a recent prospective trial in which adrenalectomy cured only 30% of 78 patients with apparently unilateral primary aldosteronism, somatic KCNJ5 and CACNA1D mutations of the aldosterone-producing adenoma (APA) had opposite influences on rates of biochemical and clinical success. We sought explanations in the bulk and single-cell gene expression profiles of the resected APAs. The most significantly differentially expressed transcripts were CCM2L (33-fold upregulated, p=10-26), a gene linked to endothelial-cell fate with highest physiological expression in splenic sinusoidal endothelial cells; and included seven neuro-medullary genes. To trace their lineage into CACNA1D-mutant APA, we analysed 10x single-nucleus RNA-seq of 140,742 cells from 28 samples, including 3 each of a CACNA1D- and KCNJ5-mutant APA and adjacent adrenal, and a separate pair of high-definition spatial transcriptomes. CYP11B2+ve nuclei of CACNA1D-mutant but not KCNJ5-mutant APAs, and of aldosterone-producing micronodules (APM) in adjacent adrenals, were enriched for CCM2L and the neuro-medullary genes. APMs frequently harbour CACNA1D mutations and are likely the precursor of CACNA1D-mutant APAs. Hybrid cortico-endothelial and cortico-medullary cells were identified on single-nucleus and high-resolution spatial analyses, and confirmed on confocal immunofluorescence. Pseudotime trajectories and snATAC-seq analysis of adrenal and spleen placed adrenal medulla upstream of APMs, and identified chromatin accessibility in CACNA1D-mutant APA nuclei common to both splenic and adrenal endothelial nuclei. Different cells of origin for CACNA1D-mutant and KCNJ5-mutant APAs can explain the multiplicity of CACNA1D mutations in APMs and consequently poorer outcomes associated with CACNA1D-mutant APAs.</p>

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