BACKGROUND: Cancer is a complex disease that arises from the simultaneous mutations of multiple biological molecules. An effective therapeutic strategy is to exploit synthetic lethality (SL) by targeting the SL partner of cancer driver genes. Computational approaches have emerged as efficient complements to traditional methods. Although some methods integrate heterogeneous sources to learn multi-network representations, they often neglect consistent information shared across different networks and specific characteristic specific to individual network. Therefore, a comprehensive representation learning framework for capturing both multi-network consistency and network-specific information of gene pair is needed. RESULTS: We proposed a novel approach capturing Multi-network consistent and specific representation with Generative Adversarial Network for Synthetic Lethality prediction (MGANSL). MGANSL employs network-aligned and network-specific encoding modules to cooperatively learn comprehensive multi-network representations of gene pair. In particular, network-aligned encoding module can capture cross-modal consistent information via cross-network adversarial generation, and network-specific encoding module can capture single network specific information via intra-network adversarial generation. CONCLUSIONS: Comprehensive experiments conducted on two human synthetic lethality datasets demonstrate the superiority of proposed method in SL prediction. Moreover, the novel predicted SL associations could aid in designing anti-cancer drugs and providing potential drug targets.

Deep learning-based computational methods have emerged as powerful tools for predicting novel drug-gene interactions. It is essential to parse the joint influence of diverse attention focuses in large complex datasets in the model's decision-making process. Here, we propose graph attention fusion with Kolmogorov-Arnold network (KAN) for drug-gene interaction prediction (dgKAN). This approach parses the mutual influence of heterogeneous attention in drug-gene relationships by constructing an interpretable KAN network. Specifically, we use dynamic neighbor selection module by dynamic attention sampling to construct subgraphs and generate embedding representations for drugs and genes within these subgraphs. Then, we utilize a module consisted of Transformer and GNN architectures (TransGNN) to fuse the mechanism of global attention and local attention. Finally, we develop an interpretable KAN network with spline functions to model and analyze the cross-domain information flow between drugs and genes, enabling the prediction of drug-gene interactions. We conducted comprehensive experiments on various datasets, and the results demonstrate that dgKAN outperforms other baseline methods. Meanwhile, results illustrate that dgKAN captures the implicit characteristics by parsing heterogeneous attention in drug-gene relationships. The predicted drug-gene interactions have the potential to significantly aid in drug development for disease treatment.

Cancer is a multifaceted disease that results from co-mutations of multi biological molecules. A promising strategy for cancer therapy involves in exploiting the phenomenon of Synthetic Lethality (SL) by targeting the SL partner of cancer gene. Since traditional methods for SL prediction suffer from high-cost, time-consuming and off-targets effects, computational approaches have been efficient complementary to these methods. Most of existing approaches treat SL associations as independent of other biological interaction networks, and fail to consider other information from various biological networks. Despite some approaches have integrated different networks to capture multi-modal features of genes for SL prediction, these methods implicitly assume that all sources and levels of information contribute equally to the SL associations. As such, a comprehensive and flexible framework for learning gene cross-network representations for SL prediction is still lacking. In this work, we present a novel Triple-Attention cross-network Representation learning for SL prediction (TARSL) by capturing molecular features from heterogeneous sources. We employ three-level attention modules to consider the different contribution of multi-level information. In particular, feature-level attention can capture the correlations between molecular feature and network link, node-level attention can differentiate the importance of various neighbors, and network-level attention can concentrate on important network and reduce the effects of irrelated networks. We perform comprehensive experiments on human SL datasets and these results have proven that our model is consistently superior to baseline methods and predicted SL associations could aid in designing anti-cancer drugs.

Computational drug repositioning which accelerates the process of drug development is able to reduce the cost in terms of time and money dramatically which brings promising and broad perspectives for the treatment of complex diseases. Heterogeneous networks fusion has been proposed to improve the performance of drug repositioning. Due to the difference and the specificity including the network structure and the biological function among different biological networks, it poses serious challenge on how to represent drug features and construct drug-disease associations in drug repositioning. Therefore, we proposed a novel drug repositioning method (ATDR) that employed attention transfer across different networks constructed by the deeply represented features integrated from biological networks to implement the disease-drug association prediction. Specifically, we first implemented the drug feature characterization with the graph representation of random surfing for different biological networks, respectively. Then, the drug network of deep feature representation was constructed with the aggregated drug informative features acquired by the multi-modal deep autoencoder on heterogeneous networks. Subsequently, we accomplished the drug-disease association prediction by transferring attention from the drug network to the drug-disease interaction network. We performed comprehensive experiments on different datasets and the results illustrated the outperformance of ATDR compared with other baseline methods and the predicted potential drug-disease interactions could aid in the drug development for disease treatments.

Computational methods to discover potential synthetic lethality (SL) pairs has become a promising strategy for targeted cancer therapy and cancer medicine development. Despite many computational methods by integrating multiple biological networks were proposed to improve the identification performance. It is essential to propose feature representation approach via embedding latent biological variables in various networks into a unified feature space. Therefore, we propose a method to identify synthetic lethality genes by modeling latent space with embedding variables resulting from the potential interpretation of synthetic lethality on integrating heterogeneous networks (LSTF) to obtain gene representation. Meanwhile, manifold subspace regularization is applied to capture the geometrical manifold structure in the latent space with gene PPI functional and GO semantic embeddings. Subsequently, SL gene pairs are identified by the reconstruction of the associations with gene representations in the latent space. The comprehensive experimental results illustrate that LSTF is superior to other state-of-the-art methods. Case study demonstrates the effectiveness of the identified potential SL genes.

Synthetic lethality (SL) is a potential cancer therapeutic strategy and drug discovery. Computational approaches to identify synthetic lethality genes have become an effective complement to wet experiments which are time consuming and costly. Graph convolutional networks (GCN) has been utilized to such prediction task as be good at capturing the neighborhood dependency in a graph. However, it is still a lack of the mechanism of aggregating the complementary neighboring information from various heterogeneous graphs. Here, we propose the Multiple Attention Graph Convolution Networks for predicting synthetic lethality (MAGCN). First, we obtain the functional similarity features and topological structure features of genes from different data sources respectively, such as Gene Ontology data and Protein-Protein Interaction. Then, graph convolutional network is utilized to accumulate the knowledge from neighbor nodes according to synthetic lethal associations. Meanwhile, we propose a multiple graphs attention model and construct a multiple graphs attention network to learn the contribution factors of different graphs to generate embedded representation by aggregating these graphs. Finally, the generated feature matrix is decoded to predict potential synthetic lethal interaction. Experimental results show that MAGCN is superior to other baseline methods. Case study demonstrates the ability of MAGCN to predict human SL gene pairs.

Predicting the associations of miRNAs and diseases may uncover the causation of various diseases. Many methods are emerging to tackle the sparse and unbalanced disease related miRNA prediction. Here, we propose a Probabilistic matrix decomposition combined with neighbor learning to identify MiRNA-Disease Associations utilizing heterogeneous data(PMDA). First, we build similarity networks for diseases and miRNAs, respectively, by integrating semantic information and functional interactions. Second, we construct a neighbor learning model in which the neighbor information of individual miRNA or disease is utilized to enhance the association relationship to tackle the spare problem. Third, we predict the potential association between miRNAs and diseases via probability matrix decomposition. The experimental results show that PMDA is superior to other five methods in sparse and unbalanced data. The case study shows that the new miRNA-disease interactions predicted by the PMDA are effective and the performance of the PMDA is superior to other methods.

Identifying cancer drivers is a crucial challenge to explain the underlying mechanisms of cancer development. There are many methods to identify cancer drivers based on the single mutation site or the entire gene. But they ignore a large number of functional elements with medium in size. It is hypothesized that mutations occurring in different regions of the protein sequence have different effects on the progression of cancer. Here, we develop a novel functional region driver(frDriver) identification method based on Bayesian probability and multiple linear regression models to identify protein regions that can regulate gene expression levels and have high functional impact potential. Combining gene expression data and somatic mutation data, with functional impact scores(SIFT, PROVEAN) as a priori knowledge, we identified cancer driver regions that are most accurate in predicting gene expression levels. We evaluated the performance of frDriver on the BRCA and GBM datasets from TCGA. The results showed that frDriver identified known cancer drivers and outperformed the other three state-of-the-art methods(eDriver, ActiveDriver and OncodriveCLUST). In addition, we performed KEGG pathway and GO term enrichment analysis, and the results indicated that the cancer drivers predicted by frDriver were related to processes such as cancer formation and gene regulation.

Motivation: Functional somatic mutations within coding amino acid sequences confer growth advantage in pathogenic process. Most existing methods for identifying cancer-related mutations focus on the single amino acid or the entire gene level. However, gain-of-function mutations often cluster in specific protein regions instead of existing independently in the amino acid sequences. Some approaches for identifying mutation clusters with mutation density on amino acid chain have been proposed recently. But their performance in identification of mutation clusters remains to be improved. Results: Here we present a Data-adaptive Mutation Clustering Method (DMCM), in which kernel density estimate (KDE) with a data-adaptive bandwidth is applied to estimate the mutation density, to find variable clusters with different lengths on amino acid sequences. We apply this approach in the mutation data of 571 genes in over twenty cancer types from The Cancer Genome Atlas (TCGA). We compare the DMCM with M2C, OncodriveCLUST and Pfam Domain and find that DMCM tends to identify more significant clusters. The cross-validation analysis shows DMCM is robust and cluster cancer type enrichment analysis shows that specific cancer types are enriched for specific mutation clusters. Availability and implementation: DMCM is written in Python and analysis methods of DMCM are written in R. They are all released online, available through https://github.com/XinguoLu/DMCM. Supplementary information: Supplementary data are available at Bioinformatics online.