Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing—which produces various mature mRNAs and, eventually, protein variants from a single gene—may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.
癌症驱动基因通常分为原癌基因和抑癌基因，分别通过驱动突变激活或失活。选择性剪接——从单个基因产生多种成熟mRNA并最终形成不同蛋白质变体——也可能因驱动基因变体功能各异且常相互拮抗而驱动肿瘤转化。本综述分析了导致肿瘤转化的不同选择性剪接事件，重点阐述其分子机制。为此，我们收集了568个癌症驱动基因列表，通过文献梳理筛选出两类基因：一类参与其他基因的选择性剪接调控，另一类其自身前体mRNA经历选择性剪接，两者均能产生致癌亚型。第一类包含31个基因，涉及剪接因子、剪接体组分及剪接调控因子。第二类包含168个驱动基因，其选择性剪接直接产生致癌亚型。随后我们根据产生致癌亚型的分子机制进行分组：顺式剪接调控元件突变、非突变顺式元件相关因素、剪接因子改变以及表观遗传与染色质相关变化。本综述提供的数据证实异常剪接可调控原癌基因激活或抑癌基因失活，并对40余个驱动基因的作用机制进行了详细阐述。
The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes
肿瘤(癌症)患者之家