Wnt/β-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase a signaling pathways alterations and somatic β-catenin gene mutations in the progression of adrenocortical tumors
Wnt/β-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase a signaling pathways alterations and somatic β-catenin gene mutations in the progression of adrenocortical tumors
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DOI：
10.1210/jc.2008-0631
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Bertherat, Jerome
中科院分区：
文献类型：
--
作者：
Gaujoux, Sebastien;Tissier, Frederique;Bertherat, Jerome
背景：Wnt/β-catenin和cAMP信号通路在肾上腺皮质肿瘤的发生中起重要作用。β-连环蛋白基因（CTNNB 1）的体细胞激活突变是肾上腺皮质腺瘤（ACA）和肾上腺皮质癌（ACC）中最常见的遗传缺陷。PRKAR 1A突变导致cAMP通路失调见于原发性色素性结节性肾上腺皮质疾病（PPNADs）和一些散发性ACAs.Objective：本研究的目的是研究伴有cAMP通路遗传改变的肾上腺皮质肿瘤（ACTs）中Wnt/β-连环蛋白失调，并寻找异质性肿瘤中继发性CTNNB 1体细胞突变。通过免疫组织化学和DNA测序研究了9个PPNAD，包括5个大结节，3个具有PRKAR 1A体细胞突变的ACA，以及1个ACA内发展的具有ACC的异质性肿瘤。在所有PPNAD、具有PRKAR 1A突变的ACA和异质性肿瘤的ACC组分中观察到β-连环蛋白积聚。CTNNB 1体细胞激活突变被发现在两个大结节的五个大结节PPNADs，在一个ACA与PRKAR 1A体细胞突变，并在恶性部分的异质性ACT.Conclusions：Wnt/β-catenin通路激活PPNADs和ACA与PRKAR 1A突变，表明在ACT发展的cAMP和Wnt/β-catenin通路之间的串扰。此外，CTNNB 1体细胞突变的额外发生与更大或更具侵略性的ACT相关。这强调了Wnt/β-连环蛋白通路在肾上腺皮质肿瘤发生中的重要性以及遗传积累在ACT进展中的重要性。
Background: The Wnt/beta-catenin and cAMP signaling pathways play an important role in adrenal cortex tumorigenesis. Somatic activating mutations of the beta-catenin gene (CTNNB1) are the most frequent genetic defects identified both in adrenocortical adenomas (ACAs) and adrenocortical cancers (ACCs). PRKAR1A mutations leading to cAMP pathway dysregulation are observed in primary pigmented nodular adrenocortical diseases (PPNADs) and some sporadic ACAs.Objective: The objective of the investigation was to study Wnt/beta-catenin dysregulation in adrenocortical tumors (ACTs) with cAMP pathway genetic alteration and search for secondary CTNNB1 somatic mutations in heterogeneous tumors.Patients and methods: Nine PPNADs, including five with macronodules, three ACAs with PRKAR1A somatic mutations, and one heterogeneous tumor with ACC developed within an ACA, were studied by immunohistochemistry and DNA sequencing.Results: beta-Catenin accumulation was observed in all PPNADs, ACAs with PRKAR1A mutations, and the ACC component of the heterogeneous tumor. CTNNB1 somatic activating mutations were found in the macronodule of two of the five macronodular PPNADs, in one ACA with a PRKAR1A somatic mutation, and in the malignant part of the heterogeneous ACT.Conclusions: The Wnt/beta-catenin pathway is activated in PPNADs and ACAs with PRKAR1A mutations, suggesting a cross talk between the cAMP and Wnt/beta-catenin pathways in ACT development. In addition, the occurrence as an additional hit of a CTNNB1 somatic mutation is associated with larger or more aggressive ACTs. This underlines the importance of the Wnt/beta-catenin pathway in adrenal cortex tumorigenesis and the importance of genetic accumulation in the progression of ACTs.