Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations.

癌症驱动基因可以对各种类型的遗传改变进行正向选择，包括功能获得或功能丧失突变和拷贝数改变（CNA）。我们研究了影响 17,644 个癌症外显子组和基因组中驱动基因的不同类型改变的情况。我们发现癌基因可能同时在不同的基因片段中表现出正选择和负选择的特征，这提出了一种识别其他肿瘤类型的方法，其中癌基因是驱动因素或脆弱性。接下来，我们描述了 CNA 依赖性选择效应的概况，揭示了癌基因突变的正选择增加的总体趋势，不仅在 CNA 获得时，而且在 CNA 删除时。同样，我们观察到肿瘤抑制基因的突变和 CNA 增益之间存在积极的相互作用。因此，无论 CNA 类型如何，涉及点突变和 CNA 的两次命中事件都普遍观察到，并且可能预示着新的治疗机会。重点关注体细胞 CNA 两次击中事件的分析可以帮助识别与肿瘤类型相关的其他驱动基因。通过对点突变和 CNA 选择特征及其跨基因和组织的相互作用的全局推断，我们确定了驱动基因的 9 种进化原型，代表了基因改变激活（不）激活的不同机制。