HGTDR: Advancing drug repurposing with heterogeneous graph transformers.

MOTIVATION: Drug repurposing is a viable solution for reducing the time and cost associated with drug development. However, thus far, the proposed drug repurposing approaches still need to meet expectations. Therefore, it is crucial to offer a systematic approach for drug repurposing to achieve cost savings and enhance human lives. In recent years, using biological network-based methods for drug repurposing has generated promising results. Nevertheless, these methods have limitations. Primarily, the scope of these methods is generally limited concerning the size and variety of data they can effectively handle. Another issue arises from the treatment of heterogeneous data, which needs to be addressed or converted into homogeneous data, leading to a loss of information. A significant drawback is that most of these approaches lack end-to-end functionality, necessitating manual implementation and expert knowledge in certain stages. RESULTS: We propose a new solution, Heterogeneous Graph Transformer for Drug Repurposing (HGTDR), to address the challenges associated with drug repurposing. HGTDR is a three-step approach for knowledge graph-based drug repurposing: (1) constructing a heterogeneous knowledge graph, (2) utilizing a heterogeneous graph transformer network, and (3) computing relationship scores using a fully connected network. By leveraging HGTDR, users gain the ability to manipulate input graphs, extract information from diverse entities, and obtain their desired output. In the evaluation step, we demonstrate that HGTDR performs comparably to previous methods. Furthermore, we review medical studies to validate our method's top 10 drug repurposing suggestions, which have exhibited promising results. We also demonstrated HGTDR's capability to predict other types of relations through numerical and experimental validation, such as drug-protein and disease-protein inter-relations. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/bcb-sut/HGTDR and http://git.dml.ir/BCB/HGTDR.

Pan-cancer integrative analysis of whole-genome De novo somatic point mutations reveals 17 cancer types.

BACKGROUND: The advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, identifying many cancer-associated genes. Although cancers in the same tissue are widely categorized in the same group, they demonstrate many differences concerning their mutational profiles. Hence, there is no definitive treatment for most cancer types. This reveals the importance of developing new pipelines to identify cancer-associated genes accurately and re-classify patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types. RESULTS: In this study, we propose a new machine learning pipeline to identify protein-coding genes mutated in many samples to identify cancer subtypes. We apply our pipeline to 12,270 samples collected from the international cancer genome consortium, covering 19 cancer types. As a result, we identify 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways. CONCLUSIONS: This new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. Additionally, we analyze the mutational signatures for samples in each subtype, which provides important insight into their active molecular mechanisms. Some of the pathways we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rates of mutation in multiple cancer subtypes. In addition, our study on "gene-motif" suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer .

Whole-Genome Analysis of De Novo Somatic Point Mutations Reveals Novel Mutational Biomarkers in Pancreatic Cancer.

It is now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.