Nonstop or stop-loss mutations convert a stop into a sense codon, resulting in translation into the 3′ untranslated region as a nonstop extension mutation to the next in-frame stop codon or as a readthrough mutation into the poly-A tail. Nonstop mutations have been characterized in hereditary diseases, but not in cancer genetics. In a pan-cancer analysis, we curated and analysed 3,412 nonstop mutations from 62 tumour entities, generating a comprehensive database at http://NonStopDB.dkfz.de. Six different nonstop extension mutations affected the tumour suppressor SMAD4, extending its carboxy terminus by 40 amino acids. These caused rapid degradation of the SMAD4 mutants via the ubiquitin–proteasome system. A hydrophobic degron signal sequence of ten amino acids within the carboxy-terminal extension was required to induce complete loss of the SMAD4 protein. Thus, we discovered that nonstop mutations can be functionally important in cancer and characterize their loss-of-function impact on the tumour suppressor SMAD4.

不间断或终止丢失突变将终止转换为有义密码子，导致翻译为 3' 非翻译区，作为下一个框内终止密码子的不间断延伸突变或作为 poly-A 尾的通读突变。不间断突变已在遗传性疾病中得到表征，但在癌症遗传学中却没有。在泛癌分析中，我们策划并分析了来自 62 个肿瘤实体的 3,412 个不间断突变，在 http://NonStopDB.dkfz.de 生成了一个综合数据库。六种不同的不间断延伸突变影响肿瘤抑制基因 SMAD4，将其羧基末端延伸 40 个氨基酸。这些通过泛素-蛋白酶体系统导致 SMAD4 突变体的快速降解。需要羧基末端延伸内的十个氨基酸的疏水性degron信号序列来诱导SMAD4蛋白的完全丧失。因此，我们发现不间断突变在癌症中可能在功能上很重要，并描述了它们对肿瘤抑制因子 SMAD4 的功能丧失影响。