Prevalence of Somatic Mutations in Aldosterone-Producing Adenomas in Japanese Patients

Abstract

Context Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among aldosterone-producing adenoma (APA) patients. For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare. Objectives To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach. Method Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing. Results CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including two previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs. 60% (41/68); P&0.0001]. Conclusion IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients.

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

“…For this reason, the pathogenesis of benign aldosterone-producing adrenal cortical disease (e.g., APA, APM/ APCC, APN) is typically linked to somatic mutations in several ion channels (Fig. 3) including the potassium channel mutation-KCNJ5 (encodes G-protein activated inward rectifier potassium channel 4; GIRK4) [30,31], sodium/ potassium ATPase mutation-ATP1A1 (encodes alpha-1 subunit of the sodium/potassium ATPase) [31][32][33], calcium ATPase mutation-ATP2B3 (encodes the plasma cell membrane calcium ATPase isoform; PMCA3) [31,32], voltagedependent calcium channel subunit mutations including the high-voltage activated L-type subunit-CACNA1D (encodes Ca v 1.3) [33][34][35] and the low-voltage activated T-type subunit-CACNA1H (encodes Ca v 3.2) [35,36], and the recently described voltage-gated chloride channel mutation-CLCN2 (encodes CIC-2) [37].…”

Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies

“…APAs with these mutations are likely to consist of ZF-like clear cells than others, and ZF cells are responsible for cortisol secretion and express a higher level of ACTH receptor than ZG cells ( 59 , 60 ). Given that nearly 90% of APAs had somatic mutations based on the CYP11B2 immunohistochemistry-guided, full gene-based next-generation sequencing ( 61 – 63 ), future multi-center studies are warranted to identify the heterogeneous aldosterone response to synthetic ACTH by these genetic mutations.…”

“…Sampling bias needs to be considered in almost all studies (including clinical trials) because the study sample is often different from the population to which clinical interventions or guidelines are targeted in the real-world. This bias requires attention in PA studies given the different prevalence of PA/SH and somatic mutations in APA across countries ( 62 , 63 , 76 ); i.e., study results from a specific region may not simply be applied to other regions. Moreover, as shown in our literature review, some topic has tended to be heavily interested in a specific region or country, that also limits the external validity.…”

Recent Development toward the Next Clinical Practice of Primary Aldosteronism: A Literature Review

“…On the other hand, aberrant immunolocalization pattern of steroidogenic enzymes was reported to be one of the characteristics of neoplastic aldosterone-producing lesions [ 71 ]. In addition, their association with genotypes has been also reported as the characteristic of the disease, which is also different dependent on the ethnicity i.e., KCNJ5 mutation was detected in more than 70% in East Asian cohorts [ 76 , 77 , 78 , 79 , 80 ], 40% in Caucasian [ 81 ], while CACNA1D was most frequently detected (≈40%) in Afro-America [ 82 ]. Of particular interest, 10–20% of APAs have been reported to complicate with cortisol excess, especially detected in large-sized tumors [ 83 , 84 ].…”

“…A remaining issue to be discussed is further validation of the steroid panel specific for region and race. Considering the regional and racial characteristics in the prevalence of APA genotypes [ 80 , 81 , 82 ], optimization of the steroid assessment should be performed at each region. Additionally, reproducibility of the steroid profiles in PA remains unclear.…”