Division of Endocrinology, Department of Medicine, Centre Hospitalier de l'Université de Montréal, Hôtel-Dieu, 3850 Saint Urbain Street, Montréal, Québec, Canada H2W 1T7.
J Clin Endocrinol Metab. 2011 Sep;96(9):E1477-81. doi: 10.1210/jc.2010-2987. Epub 2011 Jul 6.
Mutations of the β-catenin gene (CTNNB1), which lead to constitutive activation of Wnt signaling, have recently been described in adrenocortical adenomas (AA) and carcinomas (ACC). However, somatic CTNNB1 mutations may explain only about 50% of β-catenin accumulation observed in adrenocortical tumors, indicating that other components of the Wnt pathway may be involved.
The objective of the study was to investigate whether alterations in AXIN2 may be present in adrenocortical tumors.
We studied 49 human adrenocortical samples: 30 AA, six ACC, five primary pigmented nodular adrenocortical disease five ACTH-independent macronodular adrenal hyperplasias (AIMAH), and three ACTH-dependent hyperplasias in addition to the human ACC cell lines SW13 and H295R. Samples were screened for somatic genetic alterations in exon 3 of CTNNB1 and exons 5, 7, and 9 of AXIN2.
We found an in-frame, 12-bp deletion beginning at coding nucleotide 2013 in exon 7 of the AXIN2 gene, c.2013_2024del12 (p.Arg671_Pro674del), in two of 30 AA (7%), one of six ACC (17%), and the ACC H295R cell line. Immunohistochemistry revealed that tumors with AXIN2 genetic defects showed nuclear/cytoplasmic accumulation of β-catenin, indicating the activation of Wnt signaling. In addition, the ACC and H295R cells with AXIN2 deletion (c.2013_2024del12) harbored p.Ser45del and p.Ser45Pro CTNNB1 mutations, respectively. Two single-nucleotide polymorphisms were identified in exon 7 of AXIN2, c.2351C>T in 2 AA, and one AIMAH and c.2342A>G in an AIMAH tissue.
The present study reports, for the first time, that AXIN2 genetic defects may be found in adrenocortical tumors. However, the functional consequence of this genetic alteration remains to be determined.
β-连环蛋白基因（CTNNB1）的突变导致 Wnt 信号的组成性激活，最近在肾上腺皮质腺瘤（AA）和癌（ACC）中被描述。然而，体细胞 CTNNB1 突变可能仅解释了在肾上腺皮质肿瘤中观察到的β-连环蛋白积累的约 50%，这表明 Wnt 途径的其他成分可能参与其中。
本研究的目的是研究 AXIN2 的改变是否存在于肾上腺皮质肿瘤中。
我们研究了 49 个人类肾上腺皮质样本：30 个 AA、6 个 ACC、5 个原发性色素性结节性肾上腺皮质病、5 个 ACTH 非依赖性大结节性肾上腺增生（AIMAH）和 3 个 ACTH 依赖性增生，此外还有人 ACC 细胞系 SW13 和 H295R。对 CTNNB1 外显子 3 和 AXIN2 的外显子 5、7 和 9 进行了体细胞遗传改变的筛选。
我们发现 AXIN2 基因外显子 7 中从编码核苷酸 2013 开始的 12 个碱基对缺失，c.2013_2024del12（p.Arg671_Pro674del），在 30 个 AA 中的 2 个（7%）、6 个 ACC 中的 1 个（17%）和 ACC H295R 细胞系中发现。免疫组织化学显示，AXIN2 遗传缺陷的肿瘤显示β-连环蛋白的核/细胞质积累，表明 Wnt 信号的激活。此外，携带 AXIN2 缺失（c.2013_2024del12）的 ACC 和 H295R 细胞分别携带 p.Ser45del 和 p.Ser45Pro CTNNB1 突变。在 AXIN2 的外显子 7 中发现了两个单核苷酸多态性，c.2351C>T 在 2 个 AA 中，一个 AIMAH 中，c.2342A>G 在一个 AIMAH 组织中。
本研究首次报道 AXIN2 遗传缺陷可能存在于肾上腺皮质肿瘤中。然而，这种遗传改变的功能后果仍有待确定。
