The RAS and RHO family comprise two major branches of the RAS superfamily of small GTPases. These proteins function as regulated molecular switches and control cytoplasmic signaling networks that regulate a diversity of cellular processes, including cell proliferation and cell migration. In the early 1980s, mutationally activated RAS genes encoding KRAS, HRAS and NRAS were discovered in human cancer and now comprise the most frequently mutated oncogene family in cancer. Only recently, exome sequencing studies identified cancer-associated alterations in two RHO family GTPases, RAC1 and RHOA. RAS and RHO proteins share significant identity in their amino acid sequences, protein structure and biochemistry. Cancer-associated RAS mutant proteins harbor missense mutations that are found primarily at one of three mutational hotspots (G12, G13 and Q61) and have been identified as gain-of-function oncogenic alterations. Although these residues are conserved in RHO family proteins, the gain-of-function mutations found in RAC1 are found primarily at a distinct hotspot. Unexpectedly, the cancer-associated mutations found with RHOA are located at different hotspots than those found with RAS. Furthermore, since the RHOA mutations suggested a loss-of-function phenotype, it has been unclear whether RHOA functions as an oncogene or tumor suppressor in cancer development. Finally, whereas RAS mutations are found in a broad spectrum of cancer types, RHOA and RAC1 mutations occur in a highly restricted range of cancer types. In this review, we focus on RHOA missense mutations found in cancer and their role in driving tumorigenesis, with comparisons to cancer-associated mutations in RAC1 and RAS GTPases.

RAS和RHO家族是小型GTPases RAS超家族的两个主要分支。这些蛋白质起调节分子开关的作用，并控制细胞质信号网络，从而调节多种细胞过程，包括细胞增殖和细胞迁移。在1980年代初期，突变激活的RAS在人类癌症中发现了编码KRAS，HRAS和NRAS的基因，现在这些基因包括癌症中最常见的突变癌基因家族。仅在最近，外显子组测序研究才确定了两个RHO家族GTPases RAC1和RHOA中与癌症相关的改变。RAS和RHO蛋白在氨基酸序列，蛋白结构和生物化学上具有重要的同一性。与癌症相关的RAS突变蛋白具有错义突变，其主要在三个突变热点（G12，G13和Q61）之一处发现，并且已被确认为功能获得性致癌改变。尽管这些残基在RHO家族蛋白中是保守的，但在RAC1中发现的功能获得性突变主要在不同的热点处发现。不料，RHOA发现的癌症相关突变与RAS发现的突变位于不同的热点。此外，由于RHOA突变表明功能丧失的表型，因此尚不清楚RHOA是在癌症发展中起癌基因还是抑癌作用。最后，尽管在广泛的癌症类型中发现了RAS突变，但是在高度受限的癌症类型中出现了RHOA和RAC1突变。在这篇综述中，我们将重点放在在癌症中发现的RHOA错义突变及其在驱动肿瘤发生中的作用，并与RAC1和RAS GTPases中与癌症相关的突变进行比较。RAS突变存在于广泛的癌症类型中，而RHOA和RAC1突变则存在于多种癌症类型中。在这篇综述中，我们将重点放在癌症中发现的RHOA错义突变及其在驱动肿瘤发生中的作用，并与RAC1和RAS GTPases中与癌症相关的突变进行比较。RAS突变存在于广泛的癌症类型中，而RHOA和RAC1突变则存在于多种癌症类型中。在这篇综述中，我们将重点放在癌症中发现的RHOA错义突变及其在驱动肿瘤发生中的作用，并与RAC1和RAS GTPases中与癌症相关的突变进行比较。