Systematic integration of protein-affecting mutations, gene fusions, and copy number alterations into a comprehensive somatic mutational profile.
Systematic integration of protein-affecting mutations, gene fusions, and copy number alterations into a comprehensive somatic mutational profile.
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DOI：
10.1016/j.crmeth.2023.100442
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发表时间：
2023-04-24
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体细胞突变通过蛋白质影响突变（PAM）、基因融合或拷贝数改变（CNA）作为基因中的随机遗传变化发生。不同类型的突变可以具有相似的表型效应（即，等位基因异质性），并应整合到统一的基因突变谱中。我们开发了OncoMerge来填补这种整合体细胞突变的利基，以捕获等位基因异质性，为突变分配功能，并克服癌症遗传学中的已知障碍。将OncoMerge应用于TCGA泛癌症图谱增加了体细胞突变基因的检测，并改善了体细胞突变作用的预测，如激活或功能丧失。使用整合的体细胞突变矩阵增加了推断基因调控网络的能力，并发现了开关样反馈基序和延迟诱导前馈回路的富集。这些研究表明，OncoMerge有效地整合了PAM，融合和CNA，并加强了将体细胞突变与癌症表型联系起来的下游分析。OncoMerge整合了CNA、影响蛋白质的突变和基因融合与OncoMerge的整合增加了体细胞突变的检测。整合体细胞突变增强了基因调控网络的推断。癌症中的基因功能可以通过影响蛋白质的突变、拷贝数改变和基因融合来改变，从而将体细胞突变效应的信号在突变类型之间分开。我们开发了OncoMerge，将这三种突变类型系统地整合到一个单一的突变谱中，从而更好地捕捉体细胞突变对癌症表型的影响。作为一种工具，OncoMerge填补了复杂的变异识别管道和下游分析之间的差距。不同类型的体细胞突变已被证明在功能上影响肿瘤生物学。Striker等人提供了一种严格的方法，用于将影响蛋白质的突变、CNA和基因融合结合成一个完整的突变谱，用于下游研究，如基因调控网络推断。
Somatic mutations occur as random genetic changes in genes through protein-affecting mutations (PAMs), gene fusions, or copy number alterations (CNAs). Mutations of different types can have a similar phenotypic effect (i.e., allelic heterogeneity) and should be integrated into a unified gene mutation profile. We developed OncoMerge to fill this niche of integrating somatic mutations to capture allelic heterogeneity, assign a function to mutations, and overcome known obstacles in cancer genetics. Application of OncoMerge to TCGA Pan-Cancer Atlas increased detection of somatically mutated genes and improved the prediction of the somatic mutation role as either activating or loss of function. Using integrated somatic mutation matrices increased the power to infer gene regulatory networks and uncovered the enrichment of switch-like feedback motifs and delay-inducing feedforward loops. These studies demonstrate that OncoMerge efficiently integrates PAMs, fusions, and CNAs and strengthens downstream analyses linking somatic mutations to cancer phenotypes. OncoMerge integrates CNAs, protein-affecting mutations, and gene fusions Integration with OncoMerge increases detection of somatic mutations Integrating somatic mutations enhances inference of gene regulatory networks Gene function in cancer can be altered through protein-affecting mutations, copy number alterations, and gene fusions, thereby splitting the signal of the somatic mutation effect across mutation types. We developed OncoMerge to systematically integrate the three mutation types into a single mutation profile that better captures the impact of somatic mutations on cancer phenotypes. As a tool, OncoMerge fills the gap between the sophisticated variant calling pipelines and downstream analyses. Different classes of somatic mutations have been shown to functionally impact tumor biology. Striker et al. provide a rigorous method for combining protein-affecting mutations, CNAs, and gene fusions into an integrated mutation profile for downstream studies, such as gene regulatory network inference.