Cancer is the dysregulated proliferation of cells caused by acquired mutations in key driver genes. The most frequently mutated driver genes promote tumorigenesis in various organisms, cell types, and genetic backgrounds. However, recent cancer genomics studies also point to the existence of context-dependent driver gene functions, where specific mutations occur predominately or even exclusively in certain tumor types or genetic backgrounds. Here, we review examples of co-occurring and mutually exclusive driver gene mutation patterns across cancer genomes and discuss their underlying biology. While co-occurring driver genes typically activate collaborating oncogenic pathways, we identify two distinct biological categories of incompatibilities among the mutually exclusive driver genes depending on whether the mutated drivers trigger the same or divergent tumorigenic pathways. Finally, we discuss possible therapeutic avenues emerging from the study of incompatible driver gene mutations.

癌症是由关键驱动基因的获得性突变引起的细胞增殖失调。最常见的突变驱动基因促进各种生物体、细胞类型和遗传背景的肿瘤发生。然而，最近的癌症基因组学研究也指出存在依赖于环境的驱动基因功能，其中特定突变主要或什至仅发生在某些肿瘤类型或遗传背景中。在这里，我们回顾了癌症基因组中同时发生和相互排斥的驱动基因突变模式的例子，并讨论了它们的潜在生物学。虽然共同发生的驱动基因通常会激活协作的致癌途径，我们根据突变的驱动基因是否触发相同或不同的致瘤途径，确定了相互排斥的驱动基因之间不相容的两种不同的生物学类别。最后，我们讨论了从不相容的驱动基因突变研究中出现的可能的治疗途径。