1Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
2Department of Bio and Health Informatics, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
NPJ Syst Biol Appl. 2019 Aug 7;5:27. doi: 10.1038/s41540-019-0104-5. eCollection 2019.
Non-oncogene addiction (NOA) genes are essential for supporting the stress-burdened phenotype of tumours and thus vital for their survival. Although NOA genes are acknowledged to be potential drug targets, there has been no large-scale attempt to identify and characterise them as a group across cancer types. Here we provide the first method for the identification of conditional NOA genes and their rewired neighbours using a systems approach. Using copy number data and expression profiles from The Cancer Genome Atlas (TCGA) we performed comparative analyses between high and low genomic stress tumours for 15 cancer types. We identified 101 condition-specific differential coexpression modules, mapped to a high-confidence human interactome, comprising 133 candidate NOA rewiring hub genes. We observe that most modules lose coexpression in the high-stress state and that activated stress modules and hubs take part in homoeostasis maintenance processes such as chromosome segregation, oxireductase activity, mitotic checkpoint (PLK1 signalling), DNA replication initiation and synaptic signalling. We furthermore show that candidate NOA rewiring hubs are unique for each cancer type, but that their respective rewired neighbour genes largely are shared across cancer types.
非癌基因成瘾（NOA）基因对于支持肿瘤承受压力的表型至关重要，因此对其生存至关重要。尽管公认 NOA 基因是潜在的药物靶点，但尚未有大规模的尝试将它们作为一个群体在各种癌症类型中进行鉴定和特征描述。在这里，我们提供了第一种使用系统方法鉴定条件性 NOA 基因及其重布线邻居的方法。使用来自癌症基因组图谱（TCGA）的拷贝数数据和表达谱，我们针对 15 种癌症类型在高和低基因组压力肿瘤之间进行了比较分析。我们鉴定了 101 个条件特异性差异共表达模块，映射到高可信度的人类相互作用组，包括 133 个候选 NOA 重布线枢纽基因。我们观察到大多数模块在高压力状态下失去共表达，并且激活的压力模块和枢纽参与同源平衡维持过程，如染色体分离、氧化还原酶活性、有丝分裂检查点（PLK1 信号）、DNA 复制起始和突触信号。此外，我们还表明，候选 NOA 重布线枢纽基因在每种癌症类型中都是独特的，但它们各自的重布线邻居基因在很大程度上在癌症类型中共享。
