OR05-06 Genetic and Transcriptional Heterogeneity of Aldosterone-Producing Lesions in Primary Aldosteronism

Abstract Disclosure: Y. Yang: None. Y. Yan: None. T.A. Williams: None. G. Ma: None. M. Gao: None. Y. Liu: None. Z. Zhang: None. M. Sun: None. Background: The investigation of resected adrenals from patients with primary aldosteronism has revealed various aldosterone-producing lesions with distinct genotypes. These lesions may represent different stages of adenoma development. We employed genetic and spatial transcriptomic analyses to determine how transcriptomic alterations, potentially driven by aldosterone-driver mutations, may contribute to adenoma formation. Methods: Formalin-fixed paraffin-embedded adrenal sections from 53 patients with unilateral primary aldosteronism were consecutively analyzed. Aldosterone synthase immunohistochemistry-guided DNA sequencing was performed. Spatial transcriptomic analyses were conducted on 12 aldosterone-producing lesions with distinct genotypes, and integrated with public single-cell and single-nucleus transcriptomes. Results: Somatic mutations were identified in 96.6% (28/29) of aldosterone-producing adenomas (APAs) and 87.5% (14/16) of aldosterone-producing nodules, with KCNJ5 mutations being the most frequent (89.7% vs 50.0%, respectively). In aldosterone-producing micronodules (APMs), similar numbers of KCNJ5 (n=15) and CACNA1D mutations (n=12) were identified. Spatial transcriptomics revealed intratumoral transcriptional heterogeneity in APAs with KCNJ5 mutations (n=2) and identified a unique cluster of cell populations with high SHH expression. APMs with KCNJ5 (n=3), CACNA1D mutations (n=4) or no mutation detected (n=3) exhibited similar activated pathways and cell compositions. The SHH pathway was enriched exclusively at the boundaries of APMs with KCNJ5 mutations, suggesting that morphogenic signals from adjacent cells support APM-to-APA transition in the presence of the same mutation. Conclusions: Somatic KCNJ5 mutations are not rare in APMs in Chinese patients with unilateral primary aldosteronism. APAs with KCNJ5 mutations share signaling pathways with cells adjacent to APMs with KCNJ5 mutations, highlighting genotype-dependent capacities for adenoma formation. Presentation: Saturday, July 12, 2025