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，亦是导致发病与死亡的重要原因之一。为探究HNSCC的生物学基础，我们对4对肿瘤-正常组织配对样本开展了外显子组测序。在共计569个携带体细胞突变的基因中，我们筛选出40个，在额外86例HNSCC样本中开展进一步突变分析。值得注意的是，我们在细胞间黏附基因CTNNA2与CTNNA3中检测到高频突变（二者突变率均为8%）。功能研究显示，沉默CTNNA2与CTNNA3后，HNSCC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HNSCC细胞，过表达各自突变体的细胞同样表现出迁移与侵袭能力的提升。对这些突变的临床相关性分析表明，它们与不良预后密切相关。综上，上述研究结果提示CTNNA2与CTNNA3是在HNSCC中频发突变的新型抑癌基因。