In a Brazilian cohort, ATP2B3 mutations occurred in 11.29% of aldosterone-producing adenomas, significantly higher than the 4.06% seen in other ethnicities (p=0.0053).
What is the genetic spectrum of somatic drivers in aldosterone-producing adenomas and nodules in a Brazilian cohort with primary aldosteronism?
This study identifies a uniquely high frequency of ATP2B3 somatic variants in a Brazilian cohort with primary aldosteronism, highlighting the impact of population-specific genetic backgrounds on the disease.
Abstract Background The Brazilian population represents a mosaic of genetic diversity resulting from admixture ancestries. Given reported disparities in primary aldosteronism (PA) genetics across ethnicities, we investigated the genetic spectrum of aldosterone-producing adenomas (APAs) and nodules (APNs) with classical histology in a Brazilian cohort. Methods We included 62 lesions (one case with bilateral APAs) from 61 consecutive patients (median age at PA diagnosis 49 years, 59% women) with PA and classical histology, defined by CYP11B2 immunostaining (HISTALDO consensus). Somatic DNA was extracted from CYP11B2-positive areas of the dominant lesions. Hotspot regions of KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 were initially analyzed by Sanger sequencing. Whole-exome sequencing (WES) of paired somatic and germline DNA was subsequently performed in cases without driver variants. Results Histopathology showed combined APA + aldosterone-producing micronodules as the most frequent subtype (n=29, 47.54%), followed by isolated APA (n=20, 32.79%) and APN (n=5, 8.2%). Somatic PVs were identified in 82.26% of lesions: KCNJ5 (n=35, 56.45%), ATP2B3 (n=7, 11.29%), CACNA1D (n=5, 8.06%) and ATP1A1 (n=4, 6.45%). Nine novel variants were identified, including three in ATP2B3 (two exon 8 in-frame deletions and one missense), three in KCNJ5, two in CACNA1D, and one in CTNNB1. The frequency of ATP2B3 variants (11.29%) was significantly higher than that reported in other cohorts (4.06%) from different ethnicities (p=0.0053). ATP2B3-mutated tumors occurred predominantly in older men and were smaller in size compared with wild-type tumors. Rare germline CACNA1H variants were also detected in three patients. Conclusion We confirmed the predominance of known somatic drivers and identified a uniquely high frequency of ATP2B3 variants, refining their clinical phenotype. These findings underscore the influence of population-specific genetic backgrounds and expand the global understanding of PA genetics.
Guimarães et al. (2026) studied this question. In a Brazilian cohort, ATP2B3 mutations occurred in 11.29% of aldosterone-producing adenomas, significantly higher than the 4.06% seen in other ethnicities (p=0.0053).