Cell-cell adhesion genes CTNNA2 and CTNNA3 are novel tumor suppressors frequently mutated in head and neck carcinomas

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, representing a significant cause of morbidity and mortality. To explore the biological basis of HNSCC, we performed exome sequencing in four tumor-normal pairs. Among the 569 genes found to present somatic mutations, we selected 40 for further mutational analysis in 86 additional HNSCCs. Notably, we detected frequent mutations in the cell-cell adhesion genes CTNNA2 and CTNNA3 (8% in each of them). Functional studies revealed a remarkable increase in the migration and invasive ability of HNSCC cells after CTNNA2 and CTNNA3 silencing. In addition, HNSCC cells overexpressing mutated forms of each gene show increased migration and invasive ability compared to HNSCC cells overexpressing their wild-type counterparts. Analysis of the clinical relevance of these mutations demonstrated that they are associated with poor prognosis. Taken together, these findings suggest that CTNNA2 and CTNNA3 are novel tumor suppressor genes which are commonly mutated in HNSCC.

头颈部鳞状细胞癌（Head and neck squamous cell carcinoma, HNSCC）是全球第六大常见恶性肿瘤，亦是引发发病率与死亡率升高的重要诱因。为探究头颈部鳞状细胞癌的生物学基础，我们对4对肿瘤-正常组织样本开展了外显子组测序。在鉴定得到的569个体细胞突变基因中，我们选取40个，在额外的86例头颈部鳞状细胞癌样本中进行了进一步的突变分析。值得注意的是，我们在细胞-细胞黏附基因CTNNA2与CTNNA3中检测到高频突变（二者突变率均为8%）。功能实验结果显示，沉默CTNNA2与CTNNA3后，头颈部鳞状细胞癌细胞的迁移与侵袭能力显著增强。此外，相较于过表达野生型对应基因的细胞，过表达突变型CTNNA2或CTNNA3的头颈部鳞状细胞癌细胞，其迁移与侵袭能力同样得到提升。对这些突变的临床相关性分析表明，它们与不良预后显著相关。综上，上述研究结果提示CTNNA2与CTNNA3是在头颈部鳞状细胞癌中频发突变的新型肿瘤抑制基因。