Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas
Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas
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DOI：
10.1038/ncomms3531
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发表时间：
2013-10-01
影响因子：
16.6
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Fanjul-Fernandez, Miriam;Quesada, Victor;Lopez-Otin, Carlos
喉部鳞状细胞癌是一种常见和重要的致病和死亡原因。在这里，我们探讨了这种侵袭性肿瘤的生物学基础，并确定了两种细胞-细胞粘附基因在这种恶性肿瘤中反复突变。我们首先对四个喉癌及其匹配的正常组织进行外显子组测序。在发现的569个存在体细胞突变的基因中，基于它们在癌症中的复发或功能相关性，我们选择了40个基因在另外86个喉癌中进行进一步验证。我们在CTNNA2和ctnna3编码的α -连环蛋白中检测到频繁突变（90%中的14个，15%）。功能研究显示，产生CTNNA2和CTNNA3突变形式的头颈部鳞状细胞癌细胞或两种a-连环蛋白沉默的细胞的迁移和侵袭能力增加。对这些突变的临床相关性分析表明，它们与预后不良有关。我们认为CTNNA2和CTNNA3是喉癌中常见的肿瘤抑制基因突变。
Laryngeal squamous cell carcinoma is a frequent and significant cause of morbidity and mortality. Here we explore the biological basis of this aggressive tumour, and identify two cell-cell adhesion genes as recurrently mutated in this malignancy. We first perform exome sequencing of four laryngeal carcinomas and their matched normal tissues. Among the 569 genes found to present somatic mutations, and based on their recurrence or functional relevance in cancer, we select 40 for further validation in 86 additional laryngeal carcinomas. We detect frequent mutations (14 of 90, 15%) in CTNNA2 and CTNNA3-encoding alpha-catenins. Functional studies reveal an increase in the migration and invasive ability of head and neck squamous cell carcinoma cells producing mutated forms of CTNNA2 and CTNNA3 or in cells where both a-catenins are silenced. Analysis of the clinical relevance of these mutations demonstrates that they are associated with poor prognosis. We conclude that CTNNA2 and CTNNA3 are tumour suppressor genes frequently mutated in laryngeal carcinomas.