Activating mutations in CTNNB1 in aldosterone producing adenomas.
Activating mutations in CTNNB1 in aldosterone producing adenomas.
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DOI：
10.1038/srep19546
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发表时间：
2016-01-27
影响因子：
4.6
通讯作者：
Björklund P
中科院分区：
文献类型：
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作者：
Åkerström T;Maharjan R;Sven Willenberg H;Cupisti K;Ip J;Moser A;Stålberg P;Robinson B;Alexander Iwen K;Dralle H;Walz MK;Lehnert H;Sidhu S;Gomez-Sanchez C;Hellman P;Björklund P
原发性醛固酮增多症（PA）是继发性高血压的最常见原因，在未转诊的高血压患者中的患病率为5-10%。醛固酮生成腺瘤（APA）占PA病例的很大比例，并且代表了该疾病的手术可矫正形式。WNT信号通路在APA中被激活。在其他肿瘤中，异常WNT信号传导的常见原因是编码β-连环蛋白的CTNNB 1基因突变。我们的目标是在198例APA的良好特征队列中筛选CTNNB 1突变。在5.1%的肿瘤中检测到体细胞CTNNB 1突变，与KCNJ 5、ATP 1A 1、ATP 2B 3和CACNA 1D突变相互排斥。所有观察到的突变都改变了外显子3中GSK 3 β结合结构域中的丝氨酸/苏氨酸残基。这些突变与稳定的β-连环蛋白和增加的AXIN 2表达相关，表明WNT信号传导的激活。通过CYP 11B 2 mRNA表达、CYP 11B 2蛋白表达和直接测定肿瘤组织中的醛固酮，我们证实了肿瘤组织中具有产生醛固酮的能力。这份报告提供了令人信服的证据，表明CTNNB 1突变引起的异常WNT信号传导发生在APA中。这也表明，组成性激活WNT通路的其他机制可能是重要的阿帕形成。
Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.