Identification of Genetic Alterations of AXIN2 Gene in Adrenocortical Tumors
Identification of Genetic Alterations of AXIN2 Gene in Adrenocortical Tumors
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DOI：
10.1210/jc.2010-2987
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发表时间：
2011-09-01
影响因子：
5.8
通讯作者：
Bourdeau, Isabelle
中科院分区：
文献类型：
--
作者：
Chapman, Audrey;Durand, Julien;Bourdeau, Isabelle
背景资料：β-连环蛋白基因（CTNNB 1）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CTNNB 1突变可能只能解释肾上腺皮质肿瘤中观察到的β-连环蛋白积聚的50%，这表明Wnt通路的其他成分可能参与其中。目的：本研究的目的是调查AXIN 2的改变是否可能存在于肾上腺皮质肿瘤中。30例AA、6例ACC、5例原发性色素性结节性肾上腺皮质疾病、5例ACTH非依赖性大结节性肾上腺增生（AIMAH）和3例ACTH依赖性增生，此外还有人ACC细胞系SW 13和H295 R。检测CTNNB 1基因第3外显子和AXIN 2基因第5、7、9外显子的体细胞遗传学改变。我们在AXIN 2基因外显子7的编码核苷酸2013处发现了一个12 bp的框内缺失，c.2013_2024del12（p.Arg671_Pro674del），在30个AA中的两个（7%）、六个ACC中的一个（17%）和ACC H295 R细胞系中。免疫组织化学显示，AXIN 2基因缺陷的肿瘤显示β-连环蛋白的细胞核/细胞质积聚，表明Wnt信号转导的激活。此外，具有AXIN 2缺失的ACC和H295 R细胞（c.2013_2024del12）分别具有p.Ser45del和p.Ser45Pro CTNNB 1突变。在AXIN 2基因第7外显子中发现2个单核苷酸多态性位点，其中2例AA中存在c.2351C>T，1例AIMAH中存在c.2342A>G。结论：本研究首次报道了AXIN 2基因在肾上腺皮质肿瘤中的遗传缺陷。然而，这种遗传改变的功能后果仍有待确定。（临床内分泌代谢杂志96：E1477-E1481，2011）
Background: Mutations of the beta-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 beta-catenin accumulation observed in adrenocortical tumors, indicating that other components of theWntpathwaymay be involved.Objective: The objective of the study was to investigate whether alterations in AXIN2 may be present in adrenocortical tumors.Methods: 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.Results: 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 beta-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.Conclusion: 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. (J Clin Endocrinol Metab 96: E1477-E1481, 2011)