Pharmacology and Cancer Biology, Duke University, Durham, United States.
Elife. 2021 May 17;10:e67172. doi: 10.7554/eLife.67172.
RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a 'tropism' towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q to biochemically less active G driver mutations, despite the carcinogen still being biased towards generating Q mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.
RAS 基因在人类癌症中经常发生突变。尽管可能存在许多种突变，但个别癌症类型通常对 RAS 突变的特定亚群具有“倾向性”。作为驱动突变，这些模式显然源自正常细胞。高致癌性 RAS 活性会导致致癌应激，而不同的致癌突变可以赋予不同的活性水平，这表明癌蛋白活性与 RAS 突变倾向性之间存在关系。在这里，我们表明，将鼠基因中的稀有密码子变为常见密码子以增加蛋白质表达，会导致致癌剂尿烷诱导的肿瘤从典型的 Q 驱动突变转变为生化活性较低的 G 驱动突变，尽管致癌剂仍然偏向于产生 Q 突变。相反，失活肿瘤抑制因子 p53 以减轻致癌应激会部分逆转这种效应，恢复 Q 突变。对这些发现的一种解释是，尿烷的 RAS 突变倾向性源于正常细胞对特定突变的选择，这些突变赋予了一个狭窄的信号传递窗口，促进增殖而不会引起致癌应激。
