Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Helen Diller Family Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Nat Rev Cancer. 2018 Dec;18(12):767-777. doi: 10.1038/s41568-018-0076-6.
The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but also the factors influencing this event, which has implications for cancer prevention. To this end, we suggest that there is a narrow window or 'sweet spot' by which oncogenic RAS signalling can promote tumour initiation in normal cells. As a consequence, RAS mutation patterns in each normal cell are a product of the specific RAS isoform mutated, as well as the position of the mutation and type of substitution to achieve an ideal level of signalling.
三种 RAS 基因——HRAS、NRAS 和 KRAS——在三分之一的人类癌症中发生突变，它们作为典型的癌基因起作用。有趣的是，RAS 突变存在相当明显的模式；在不同的癌症中，突变的同工型以及取代的位置和类型都有所不同。由于 RAS 基因是最早发生突变的基因之一，如果不是最早的话，在各种癌症中都发生了突变，了解这些突变模式的出现方式不仅可以说明癌症是如何开始的，还可以说明影响这一事件的因素，这对癌症预防具有重要意义。为此，我们提出，致癌 RAS 信号可以在正常细胞中促进肿瘤起始的时间窗口很窄，或者说“最佳时间点”很窄。因此，每个正常细胞中的 RAS 突变模式是突变的特定 RAS 同工型、突变位置和取代类型的产物，以达到理想的信号水平。
