Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (&lt;i&gt;PRKACA&lt;/i&gt;) gene in Japanese patients with several adrenal adenomas secreting cortisol [Rapid Communication]

Nakajima, Yasuyo; Okamura, Takashi; Gohko, Tamae; Satoh, Tetsurou; Hashimoto, Kazuhito; Shibusawa, Nobuyuki; Ozawa, Atsushi; Ishii, Sumiyasu; Tomaru, Takuya; Horiguchi, Kazuhiko; Okada, Shuichi; Takata, Daisuke; Rokutanda, Nana; Horiguchi, Jun; Tsushima, Yoshito; Oyama, Tetsunari; Takeyoshi, Izumi; Yamada, Masanobu

doi:10.1507/endocrj.ej14-0282

Cited by 32 publications

(39 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found KCNJ5 mutations in tumors predominantly secreting aldosterone, with concomitant cortisol secretion, again in line with prior work (7,16). KCNJ5 mutations cause abnormal sodium permeability of the mutant potassium channel, leading to depolarization, activation of voltage-gated calcium channel, and calcium influx (19).…”

Section: Discussionsupporting

confidence: 92%

“…Tumors co-secreting aldosterone and cortisol carried KCNJ5 mutations (G151R and L168R) in 50% (2/4) cases (Supplementary Table 2). In contrast, none of these patients showed PRKACA mutations, in line with previously published findings (7,16). Mutations in genes other than KCNJ5 are considerably less frequent in aldosterone-producing adenomas.…”

Section: Aldosterone and Cortisol Co-secreting Adenomas Show Mutationsupporting

confidence: 92%

“…Recently, recurrent somatic mutations in cortisol-producing adenomas have been identified by next-generation sequencing and confirmed in follow-up studies (3,4,5,6,7,8). The most frequently mutated gene (35.4%, range 14.3-65.5% across published cohorts, Supplementary Table 1, see section on supplementary data given at the end of this article) is PRKACA, and almost all mutations are accounted for by a single p.Leu206Arg (L206R) substitution in the encoded catalytic subunit of PKA.…”

mentioning

confidence: 87%

“…Some of the corresponding tumors have been shown to carry activating mutations in the KCNJ5 potassium channel gene that are specific to aldosterone-producing adenomas (15,16,17). Only one study screened for PRKACA mutations in these tumors, but did not report any (7). Similarly, no PRKACA mutations were found in 20 'pure' aldosterone-secreting adenomas (3).…”

mentioning

confidence: 99%

See 3 more Smart Citations

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

Thiel

Reis

Haase

et al. 2015

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA L206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone. Design, patients, and methods: In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.Results: Among cortisol-secreting unilateral lesions without evidence of co-secretion (nZ52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1CGNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA L206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions. Conclusions: PRKACA L206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Aldosterone and Cortisol Co-secreting Adenomas Show Mutationsupporting

confidence: 92%

mentioning

confidence: 87%

mentioning

confidence: 99%

See 2 more Smart Citations

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

Thiel

Reis

Haase

et al. 2015

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…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%

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

et al. 2017

Self Cite

View full text Add to dashboard Cite

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.

show abstract