GNAS mutations in adrenal aldosterone-producing adenomas [Rapid Communication]

Nakajima, Yasuyo; Okamura, Takashi; Horiguchi, Kazuhiko; Gohko, Tamae; Miyamoto, T.; Satoh, Tetsurou; Ozawa, Atsushi; Ishii, Sumiyasu; Yamada, Eijiro; Hashimoto, Kazuhito; Okada, Shuichi; Takata, Daisuke; Horiguchi, Jun; Yamada, Masanobu

doi:10.1507/endocrj.ej15-0642

Cited by 21 publications

(18 citation statements)

References 22 publications

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“…As noticed, the prevalence of KCNJ5 mutations is higher in Asia than in Western countries. We first confirmed previous findings showing a high prevalence of the KCNJ5 gene (76.3%) in Japanese patients with APAs after the addition of recent cases [7,[11][12][13]. In addition, Kitamoto et al reported a prevalence of 69.4% in Japanese [31], 59.5% in Taiwanese [29], 71.2% in Korean [30], and 76.8% in Chinese patients with APAs [28].…”

Section: Discussionsupporting

confidence: 90%

“…Boulkroun et al, who examined the large number of APA cases to date, 380, found that 129 patients (34%) had mutations in Europe [9]. We found a higher frequency, 24 out of 33 (approximately 73%) APAs, in Japan [7,[11][12][13]. Several differences of clinical features have been reported between Japanese and Western APA patients.…”

Section: Immunohistochemistrysupporting

confidence: 56%

“…Several investigators including us have since confirmed these mutations in different countries [8,9,[11][12][13]22 [32]. Therefore, the overall prevalence of KCNJ5 mutations in APAs in Western countries is approximately 35~45%.…”

Section: Discussionmentioning

confidence: 84%

“…In Japan, APA is frequently associated with the mild co-secretion of cortisol [12,13,[19][20][21]. We previously reported three PA cases that strongly secreted cortisol and found KCNJ5 mutations in 2 cases, suggesting that these tumors are derived from APA because no mutations have been identified in cortisol-producing adenomas [11].…”

Section: Discussionmentioning

confidence: 99%

“…Thirty-three patients had been included in our previous study [7,[11][12][13]. Each subject was given written informed consent, and the study was approved by the Ethics Committee on human research of Gunma University.…”

Section: Subjectsmentioning

confidence: 99%

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Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

et al. 2017

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PRIMARY ALDOSTERONISM (PA) has been reported to affect at least 6~10% of patients with essential hypertension [1][2][3][4][5] and is caused mostly by an adrenal adenoma (aldosterone-producing adenoma, APA) or by adrenal hyperplasia (idiopathic hyperaldosteronism, IHA). Although the tumorigenesis of APA remained unclear, somatic mutations of the potassium Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations Abstract. Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol cosecretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

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Section: Discussionsupporting

confidence: 90%

Section: Immunohistochemistrysupporting

confidence: 56%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

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Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

et al. 2017

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Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas

et al. 2022

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Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

et al. 2017

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Purpose Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined. The aims of our study were: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth. Methods Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated. Results Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACA p.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1 p. Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations. Conclusions The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation.

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GNAS mutations in adrenal aldosterone-producing adenomas [Rapid Communication]

Cited by 21 publications

References 22 publications

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas

Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

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