Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Cancer Research Institute, College of Medicine, The Catholic University of Korea, 222 Bandodae-ro, Seocho-Gu, Seoul, Korea.
Genome Med. 2024 Aug 19;16(1):103. doi: 10.1186/s13073-024-01376-7.
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.
确定体细胞突变的影响需要了解获得突变的基因之间的功能关系；然而，功能相关基因的突变如何相互影响在很大程度上尚不清楚。
我们采用非同义到同义或 dNdS 比值来评估基因对的进化依赖性 (ED)，假设基因对中一个基因的突变可以影响其伙伴基因突变的进化适应性，作为突变背景。我们采用泛癌和肿瘤类型特异性突变谱来推断基因对的 ED，并根据基因依赖性和药物敏感性评估其生物学相关性。
我们提出，基因对的 dNdS 比值及其衍生的 cdNS（依赖于上下文的 dNdS）评分作为 ED 的度量，可以区分协同 (SYN) 或拮抗 (ANT) 的基因对。突变背景可以导致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 缺失和 IDH1 错义突变的 dNdS 比值显著增加和减少，对应于 SYN 和 ANT 关系，具有正和负的 cdNS 评分。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 可以指导合成致死性候选物的选择，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作用通常与表现出 ED 的基因的突变相关，为靶向抑制剂提供了敏感或耐药突变信息，例如，PRSS1 和 CTCF 突变分别作为肺腺癌和黑色素瘤中 EGFR 和 BRAF 抑制剂的耐药突变。
我们提出，通过 dNdS 比值评估的基因对的 ED 可以增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。
