确定体细胞突变的影响需要了解获得突变的基因的功能关系；然而，功能相关基因中的突变如何相互影响很大程度上尚不清楚。我们采用非同义与同义比率或 dNdS 比率来评估基因对的进化依赖性（ED），假设一对基因中的一个基因发生突变可以影响其伴侣基因中突变作为突变背景的进化适应性。我们利用泛癌和肿瘤类型特异性突变谱来推断基因对的 ED，并评估它们在基因依赖性和药物敏感性方面的生物学相关性。我们提出基因对的 dNdS 比率及其衍生的 cdNS（上下文依赖的 dNdS）分数作为 ED 区分基因对作为协同 (SYN) 或拮抗 (ANT) 的衡量标准。突变背景可以诱导配对基因中突变的进化适应性发生实质性变化，例如，IDH1和IDH2突变背景导致ATRX indels和IDH1错义突变的dNdS比率大幅增加和减少，对应于SYN和ANT的正负关系分别是 cdNS 分数。基因沉默或敲除对细胞活力（遗传依赖性）的影响通常取决于 ED，这表明 ED 可以指导合成致死候选者的选择，例如 TCF7L2-KRAS 突变。使用基于细胞系的药物敏感性数据，靶向药物对细胞系的影响通常与与靶基因表现出 ED 的基因突变相关，从而告知靶向抑制剂的药物敏化或耐药突变，例如，PRSS1 和 CTCF 突变作为耐药突变分别针对肺腺癌和黑色素瘤的 EGFR 和 BRAF 抑制剂。我们提出，通过 dNdS 比率评估基因对的 ED 可以促进我们对具有潜在生物学和临床意义的基因功能关系的理解。© 2024。作者。

Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.© 2024. The Author(s).