The Journal of clinical endocrinology and metabolism · 2026
Somatic Drivers in Aldosterone-producing Adenomas and Nodules: Insights from a Brazilian Cohort of Primary Aldosteronism.
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Guimaraes Augusto G, Goldbaum Tatiana S, Ledesma Felipe L, Freitas-Castro Felipe, Santana Lucas S, Sobrinho Jose Antonio B L, Rossetti Lucas B, Okubo Jessica, Kawahara Eduardo Z, Bortolotto Luiz A, Srougi Victor, Tanno Fabio Y, Nahas Williams C, Chambo Jose L, Pereira Maria Adelaide A, Pio-Abreu Andrea, Silva Giovanio V, Drager Luciano F, Fragoso Maria Candida B V, Latronico Ana Claudia, Mendonca Berenice B, Zerbini Maria Claudia N, Almeida Madson Q
Аннотация
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 (1 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 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 pathogenic variants 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 3 in ATP2B3 (2 exon 8 in-frame deletions and 1 missense), 3 in KCNJ5, 2 in CACNA1D, and 1 in CTNNB1. The frequency of ATP2B3 variants (11.29%) was significantly higher than that reported in other cohorts (4.06%) from different ethnicities (p = .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 3 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.
METHODS: We included 62 lesions (1 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 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 pathogenic variants 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 3 in ATP2B3 (2 exon 8 in-frame deletions and 1 missense), 3 in KCNJ5, 2 in CACNA1D, and 1 in CTNNB1. The frequency of ATP2B3 variants (11.29%) was significantly higher than that reported in other cohorts (4.06%) from different ethnicities (p = .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 3 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.
Предметные рубрики MeSH
HumansFemaleHyperaldosteronismMiddle AgedMaleBrazilAdultAdrenocortical AdenomaAldosteroneAdrenal Cortex NeoplasmsCalcium Channels, L-TypePlasma Membrane Calcium-Transporting ATPasesG Protein-Coupled Inwardly-Rectifying Potassium ChannelsCohort StudiesMutationbeta CateninSodium-Potassium-Exchanging ATPaseAged