癌症驱动基因是癌基因或肿瘤抑制基因,经典激活或失活,分别,通过驱动突变。选择性剪接-产生各种成熟的mRNA和,最终,来自单个基因的蛋白质变体也可能导致驱动肿瘤转化,因为驱动基因变体的不同且通常相反的功能。本综述分析了导致肿瘤转化的不同选择性剪接事件,强调它们的分子机制。要做到这一点,我们收集了568个癌症基因驱动因素的列表,并修订了文献,以选择那些参与其他基因的可变剪接以及其前mRNA经受可变剪接的基因。结果,在这两种情况下,产生致癌同工型。31个基因属于第一类,其中包括剪接体和剪接调节器的剪接因子和成分。在第二类中,即包含驱动基因,其中可变剪接产生致癌同工型,共发现168个基因。然后,我们根据负责选择性剪接产生致癌亚型的分子机制对它们进行分组,即,顺式剪接决定元件中的突变,其他涉及非突变顺式元素的原因,剪接因子的变化,以及表观遗传和染色质相关的变化。本综述中给出的数据证实了异常剪接可能调节原癌基因的激活或肿瘤抑制基因的失活的观点,并给出了40多个驱动基因的相关机制细节。
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.