The identification of cancer driver genes is crucial for understanding the complex processes involved in cancer development, progression, and therapeutic strategies. Multi-omics data and biological networks provided by numerous databases enable the application of graph deep learning techniques that incorporate network structures into the deep learning framework. However, most existing methods do not account for the heterophily in the biological networks, which hinders the improvement of model performance. Meanwhile, feature confusion often arises in models based on graph neural networks in such graphs. To address this, we propose a Simplified Graph neural network for identifying Cancer Driver genes in heterophilic networks (SGCD), which comprises primarily two components: a graph convolutional neural network with representation separation and a bimodal feature extractor. The results demonstrate that SGCD not only performs exceptionally well but also exhibits robust discriminative capabilities compared to state-of-the-art methods across all benchmark datasets. Moreover, subsequent interpretability experiments on both the model and biological aspects provide compelling evidence supporting the reliability of SGCD. Additionally, the model can dissect gene modules, revealing clearer connections between driver genes in cancers. We are confident that SGCD holds potential in the field of precision oncology and may be applied to prognosticate biomarkers for a wide range of complex diseases.
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Commun Biol
January 2025
Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Boulder, CO, USA.
Symbioses are major drivers of organismal diversification and phenotypic innovation. However, how long-term symbioses shape whole genome evolution in metazoans is still underexplored. Here, we use a giant clam (Tridacna maxima) genome to demonstrate how symbiosis has left complex signatures in an animal's genome.
View Article and Find Full Text PDFNat Commun
January 2025
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, China.
The relative contributions of mutation rate variation, selection, and recombination in shaping genomic variation in bacterial populations remain poorly understood. Here we analyze 3318 Yersinia pestis genomes, spanning nearly a century and including 2336 newly sequenced strains, to shed light on the patterns of genetic diversity and variation distribution at the population level. We identify 45 genomic regions ("hot regions", HRs) that, although comprising a minor fraction of the genome, are hotbeds of genetic variation.
View Article and Find Full Text PDFMol Oncol
January 2025
Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Germany.
Hypermethylation of tumor suppressor genes is a hallmark of leukemia. The hypomethylating agent decitabine covalently binds, and degrades DNA (cytosine-5)-methyltransferase 1 (DNMT1). Structural similarities within DNA-binding domains of DNMT1, and the leukemic driver histone-lysine N-methyltransferase 2A (KMT2A) suggest that decitabine might also affect the latter.
View Article and Find Full Text PDFNat Genet
January 2025
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).
View Article and Find Full Text PDFNat Cancer
January 2025
Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.
CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data.
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