It is well known that in cancer gene families some members are more frequently mutated in tumor samples than their family counterparts. A paradigmatic case of this phenomenon is KRAS from the RAS family. Different explanations have been proposed ranging from differential interaction with other proteins to preferential expression or localization. Interestingly, it has been described that despite the high amino acid identity between RAS family members, KRAS employs an intriguing differential codon usage. Here, we found that this phenomenon is not exclusive to the RAS family. Indeed, in the RAS family and other oncogene families with two or three members, the most prevalently mutated gene in tumor samples employs a differential codon usage that is characteristic of genes involved in proliferation. Prompted by these observations, we chose the RAS family to experimentally demonstrate that the translation efficiency of oncogenes that are preferentially mutated in tumor samples is increased in proliferative cells compared to quiescent cells. These results were further validated by assessing the translation efficiency of KRAS in cell lines that differ in their tRNA expression profile. These differences are related to the cell division rate of the studied cells and thus suggest an important role in context-specific oncogene expression regulation. Altogether, our study demonstrates that dynamic translation programs contribute to shaping the expression profiles of oncogenes. Therefore, we propose this codon bias as a regulatory layer to control cell context-specific expression and explain the differential prevalence of mutations in certain members of oncogene families.

众所周知，在癌症基因家族中，某些成员比其家族成员更经常在肿瘤样本中发生突变。这种现象的一个典型案例是RAS家族的KRAS。已经提出了不同的解释，范围从与其他蛋白质的差异相互作用到优先表达或定位。有趣的是，已经描述了尽管RAS家族成员之间具有很高的氨基酸同一性，但KRAS还是采用了一种有趣的差异密码子用法。在这里，我们发现这种现象并非RAS系列独有。实际上，在具有两个或三个成员的RAS家族和其他癌基因家族中，肿瘤样品中最普遍突变的基因采用了不同的密码子用法，这是参与增殖的基因的特征。这些观察提示，我们选择RAS家族进行实验证明，在肿瘤样品中优先突变的癌基因的翻译效率与静止细胞相比在增生细胞中有所提高。通过评估KRAS在tRNA表达谱不同的细胞系中的翻译效率，进一步验证了这些结果。这些差异与所研究细胞的细胞分裂速率有关，因此表明在特定背景的癌基因表达调控中的重要作用。总之，我们的研究表明动态翻译程序有助于塑造癌基因的表达谱。因此，我们建议这种密码子偏倚作为控制细胞背景特定表达的调节层，并解释在癌基因家族某些成员中突变的差异流行。