Genetic and Clinical Correlations in Aldosterone-Producing Adenomas

Presentation Number: SUN 532
Date of Presentation: April 2nd, 2017

Leticia A P Vilela*1, Luiz A. Bortolotto2, Luciano Drager3, Beatriz M P Mariani2, Antonio M Lerario4, Gabriela R V Sousa5, Giovanio V. Silva3, Andrea P. Abreu3, Maria Claudia N Zerbini2, Francisco C. Carnevale3, Aline C B Santos2, Bruna Pilan2, Victor Srougi3, Fabio Y. Tanno2, Jose Luiz Chambo2, Ana Claudia Latronico6, Berenice Bilharinho Mendonça7, Maria Candida B V Fragoso8 and Madson Q. Almeida9
1Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, 2Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 3Faculdade de Medicina da Universidade de São Paulo, São Paulo, 4University of Michigan, Ann Arbor, MI, 5Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 6Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 7Hospital das Clinicas University of Sao Paulo, Sao Paulo, Brazil, 8Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 9Hospital das Clínicas & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil


Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, causative somatic mutations in key proteins of adrenal zona glomerulosa cells have been detected in aldosterone-producing adenomas (APAs). Somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in 38%, 9.3%, 5.3% and 1.7% of APAs, respectively (1). Somatic activating mutations in exon 3 of CTNNB1 gene were identified in 3 APAs diagnosed in women with PA, two presented in pregnancy and one presented after menopause (2). The Wnt pathway, through β-catenin signaling, is critical for normal adrenocortical development and maintenance. In this study, we investigated the presence of KCNJ5, ATP1A1, ATP2B3 and CTNNB1 somatic mutations in a Brazilian cohort of 50 APAs and correlated the mutational status with the clinical and hormonal parameters. Mutational hot spots of KCNJ5, ATP1A1, ATP2B3 and CTNNB1 genes were successfully sequenced by Sanger in APAs [56% female; median age at diagnosis, 49 yr (20 to 68)]. All patients included had biochemical cure of PA after surgery. Somatic heterozygous mutations were identified in 28 out of 50 (56%) APAs. KCNJ5 mutations were detected in 23 out of 50 (46%) APAs. Two recurrent mutations were found in KCNJ5: the p.Gly151Arg in 11 out of 23 (48%) and the p.Leu168Arg in 12 out of 23 (52%) APAs. Regarding the other genes: the p.Leu104Arg ATP1A1 mutation was detected in two APAs (4%); the p.Leu425_Val426del ATP2B3 mutation in one APA (2%); and the p.Ser45Pro CTNNB1 mutation in two APAs (4%). APAs harboring somatic KCNJ5 mutations were diagnosed more often in females (74% vs. 41%; X2= 5.54, p= 0.019) and at younger ages [42 yr (20 to 68) vs. 53 yr (33 to 68); p= 0.007] when compared to KCNJ5 WT APAs. The tumor size was larger in KCNJ5 mutant APAs [2.0 cm (0.7 to 3.5) vs. 1.35 cm (0.7 to 2.9); p=0.012]. Interestingly, the postoperative cure of hypertension was observed in 8 out of 22 (36%) patients with APAs harboring a somatic KCNJ5 mutation (X2= 8.27, p= 0.004), whereas only one out of 26 (3.8%) patients with KCNJ5 WT APAs normalized blood pressure without medication. The median follow-up for patients with mutant KCNJ5 and WT APAs was 28 and 22 months, respectively. Preoperative aldosterone levels and frequency of hypokalemia were not affected by KCNJ5 mutational status. In conclusion, KCNJ5 mutations were identified in 46% of APAs, with the p.Leu168Arg and p.Gly151Arg mutations presenting similar frequency. Interestingly, somatic KCNJ5 mutations were associated with a significantly higher frequency of postoperative cure of hypertension impacting follow up care of those patients.