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Novel ratio-metric features enable the identification of new driver genes across cancer types.

ABSTRACT: An emergent area of cancer genomics is the identification of driver genes. Driver genes confer a selective growth advantage to the cell. While several driver genes have been discovered, many remain undiscovered, especially those mutated at a low frequency across samples. This study defines new features and builds a pan-cancer model, cTaG, to identify new driver genes. The features capture the functional impact of the mutations as well as their recurrence across samples, which helps build a model unbiased to genes with low frequency. The model classifies genes into the functional categories of driver genes, tumour suppressor genes (TSGs) and oncogenes (OGs), having distinct mutation type profiles. We overcome overfitting and show that certain mutation types, such as nonsense mutations, are more important for classification. Further, cTaG was employed to identify tissue-specific driver genes. Some known cancer driver genes predicted by cTaG as TSGs with high probability are ARID1A, TP53, and RB1. In addition to these known genes, potential driver genes predicted are CD36, ZNF750 and ARHGAP35 as TSGs and TAB3 as an oncogene. Overall, our approach surmounts the issue of low recall and bias towards genes with high mutation rates and predicts potential new driver genes for further experimental screening. cTaG is available at https://github.com/RamanLab/cTaG .

SUBMITTER: Sudhakar M

PROVIDER: S-EPMC8741763 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Machine learning approaches to predict essential genes have gained a lot of traction in recent years. These approaches predominantly make use of sequence and network-based features to predict essential genes. However, the scope of network-based features used by the existing approaches is very narrow. Further, many of these studies focus on predicting essential genes within the same organism, which cannot be readily used to predict essential genes across organisms. Therefore, there is clearly a need for a method that is able to predict essential genes across organisms, by leveraging network-based features. In this study, we extract several sets of network-based features from protein-protein association networks available from the STRING database. Our network features include some common measures of centrality, and also some novel recursive measures recently proposed in social network literature. We extract hundreds of network-based features from networks of 27 diverse organisms to predict the essentiality of 87000+ genes. Our results show that network-based features are statistically significantly better at classifying essential genes across diverse bacterial species, compared to the current state-of-the-art methods, which use mostly sequence and a few 'conventional' network-based features. Our diverse set of network properties gave an AUROC of 0.847 and a precision of 0.320 across 27 organisms. When we augmented the complete set of network features with sequence-derived features, we achieved an improved AUROC of 0.857 and a precision of 0.335. We also constructed a reduced set of 100 sequence and network features, which gave a comparable performance. Further, we show that our features are useful for predicting essential genes in new organisms by using leave-one-species-out validation. Our network features capture the local, global and neighbourhood properties of the network and are hence effective for prediction of essential genes across diverse organisms, even in the absence of other complex biological knowledge. Our approach can be readily exploited to predict essentiality for organisms in interactome databases such as the STRING, where both network and sequence are readily available. All codes are available at https://github.com/RamanLab/nbfpeg.

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Novel ratio-metric features enable the identification of new driver genes across cancer types.

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