pDriver: a novel method for unravelling personalized coding and miRNA cancer drivers

MOTIVATION Unravelling cancer driver genes is important in cancer research. Although computational methods have been developed to identify cancer drivers, most of them detect cancer drivers at population level. However, two patients who have the same cancer type and receive the same treatment may have different outcomes because each patient has a different genome and their disease might be driven by different driver genes. Therefore new methods are being developed for discovering cancer drivers at individual level, but existing personalised methods only focus on coding drivers while microRNAs (miRNAs) have been shown to drive cancer progression as well. Thus, novel methods are required to discover both coding and miRNA cancer drivers at individual level. RESULTS We propose the novel method, pDriver, to discover personalised cancer drivers. pDriver includes two stages: (1) Constructing gene networks for each cancer patient and (2) Discovering cancer drivers for each patient based on the constructed gene networks. To demonstrate the effectiveness of pDriver, we have applied it to five TCGA cancer datasets and compared it with the state-of-the-art methods. The result indicates that pDriver is more effective than other methods. Furthermore, pDriver can also detect miRNA cancer drivers and most of them have been confirmed to be associated with cancer by literature. We further analyse the predicted personalised drivers for breast cancer patients and the result shows that they are significantly enriched in many GO processes and KEGG pathways involved in breast cancer. AVAILABILITY AND IMPLEMENTATION pDriver is available at https://github.com/pvvhoang/pDriver. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

[1]  D. Ciocca,et al.  Estrogen Receptors and Cell Proliferation in Breast Cancer , 1997, Trends in Endocrinology & Metabolism.

[2]  Liang Han,et al.  MiR-326 regulates cell proliferation and migration in lung cancer by targeting phox2a and is regulated by HOTAIR. , 2016, American journal of cancer research.

[3]  Xing-Xing He,et al.  The emerging role of miR‐375 in cancer , 2014, International journal of cancer.

[4]  Benjamin J. Raphael,et al.  CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer , 2015, Genome Biology.

[5]  Hyunsuk Shim,et al.  Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. , 2010, Biochemical pharmacology.

[6]  Tao Zeng,et al.  A novel network control model for identifying personalized driver genes in cancer , 2019, PLoS Comput. Biol..

[7]  Juan M. Vaquerizas,et al.  A census of human transcription factors: function, expression and evolution , 2009, Nature Reviews Genetics.

[8]  Ming Lu,et al.  TransmiR: a transcription factor–microRNA regulation database , 2009, Nucleic Acids Res..

[9]  Hsien-Da Huang,et al.  miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database , 2015, Nucleic Acids Res..

[10]  Benjamin J. Raphael,et al.  Hierarchical HotNet: identifying hierarchies of altered subnetworks , 2018, Bioinform..

[11]  John Quackenbush,et al.  Estimating Sample-Specific Regulatory Networks , 2015, iScience.

[12]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[13]  D. Bartel,et al.  Predicting effective microRNA target sites in mammalian mRNAs , 2015, eLife.

[14]  K. Lukong,et al.  Signaling pathways in breast cancer: therapeutic targeting of the microenvironment. , 2014, Cellular signalling.

[15]  Sergey Brin,et al.  The Anatomy of a Large-Scale Hypertextual Web Search Engine , 1998, Comput. Networks.

[16]  A. Vinayagam,et al.  A Directed Protein Interaction Network for Investigating Intracellular Signal Transduction , 2011, Science Signaling.

[17]  Lei Zhang,et al.  Discovering personalized driver mutation profiles of single samples in cancer by network control strategy , 2018, Bioinform..

[18]  Wei Zhang,et al.  Functional analyses of microRNA-326 in breast cancer development , 2019, Bioscience reports.

[19]  Brock C Christensen,et al.  MicroRNA Expression Ratio Is Predictive of Head and Neck Squamous Cell Carcinoma , 2009, Clinical Cancer Research.

[20]  J. P. Hou,et al.  DawnRank: discovering personalized driver genes in cancer , 2014, Genome Medicine.

[21]  Andrew D. Rouillard,et al.  Enrichr: a comprehensive gene set enrichment analysis web server 2016 update , 2016, Nucleic Acids Res..

[22]  C. Sander,et al.  Genome-wide analysis of non-coding regulatory mutations in cancer , 2014, Nature Genetics.

[23]  B. Liang,et al.  A three-microRNA signature as a diagnostic and prognostic marker in clear cell renal cancer: An In Silico analysis , 2017, PloS one.

[24]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[25]  Wenjun Liu,et al.  Clinical potential of miR-940 as a diagnostic and prognostic biomarker in breast cancer patients. , 2018, Cancer biomarkers : section A of Disease markers.

[26]  I. Ebersberger,et al.  Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype , 2019, Nature Communications.

[27]  Kiwon Jang,et al.  Predicting the recurrence of noncoding regulatory mutations in cancer , 2016, BMC Bioinformatics.

[28]  Guoxin Zhang,et al.  MiR‐577 suppresses epithelial‐mesenchymal transition and metastasis of breast cancer by targeting Rab25 , 2018, Thoracic cancer.

[29]  Samuel Leung,et al.  Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than Triple-Negative Phenotype , 2008, Clinical Cancer Research.

[30]  Vu V H Pham,et al.  DriverGroup: a novel method for identifying driver gene groups. , 2020, Bioinformatics.

[31]  A. Bashashati,et al.  DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer , 2012, Genome Biology.

[32]  Xiaowei Wang,et al.  OncomiR: an online resource for exploring pan-cancer microRNA dysregulation , 2018, Bioinform..

[33]  Joshua D. Campbell,et al.  NetSig: network-based discovery from cancer genomes , 2017, Nature Methods.

[34]  Jian Pei,et al.  Continuous Influence Maximization: What Discounts Should We Offer to Social Network Users? , 2016, SIGMOD Conference.

[35]  Gary D Bader,et al.  Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers , 2013 .

[36]  R. Kálmán Mathematical description of linear dynamical systems , 1963 .

[37]  Albert-László Barabási,et al.  Controllability of complex networks , 2011, Nature.

[38]  Jiuyong Li,et al.  Computational methods for cancer driver discovery: A survey , 2020, Theranostics.

[39]  C. Sander,et al.  Mutual exclusivity analysis identifies oncogenic network modules. , 2012, Genome research.

[40]  A. Gonzalez-Perez,et al.  Functional impact bias reveals cancer drivers , 2012, Nucleic acids research.

[41]  S. Påhlman,et al.  Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors , 2012, Upsala journal of medical sciences.

[42]  Lei Wang,et al.  hsa‐mir‐3199‐2 and hsa‐mir‐1293 as Novel Prognostic Biomarkers of Papillary Renal Cell Carcinoma by COX Ratio Risk Regression Model Screening , 2017, Journal of cellular biochemistry.

[43]  H. Dweep,et al.  miRWalk2.0: a comprehensive atlas of microRNA-target interactions , 2015, Nature Methods.

[44]  Maoguo Gong,et al.  Influence maximization in social networks based on discrete particle swarm optimization , 2016, Inf. Sci..

[45]  Jiuyong Li,et al.  CBNA: A control theory based method for identifying coding and non-coding cancer drivers , 2019, PLoS Comput. Biol..

[46]  Z. Ghaemi,et al.  MicroRNA-326 Functions as a Tumor Suppressor in Breast Cancer by Targeting ErbB/PI3K Signaling Pathway , 2019, Front. Oncol..

[47]  A. Valencia,et al.  Non-coding recurrent mutations in chronic lymphocytic leukaemia , 2015, Nature.

[48]  X. Hua,et al.  DriverML: a machine learning algorithm for identifying driver genes in cancer sequencing studies , 2019, Nucleic acids research.

[49]  Finn Drabløs,et al.  Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals , 2016, Nucleic Acids Res..

[50]  Athanasios Fevgas,et al.  DIANA-TarBase v7.0: indexing more than half a million experimentally supported miRNA:mRNA interactions , 2014, Nucleic Acids Res..

[51]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer genes , 2014 .

[52]  N. Kosaka,et al.  Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A , 2018, Proceedings of the National Academy of Sciences.

[53]  David Tamborero,et al.  OncodriveCLUST: exploiting the positional clustering of somatic mutations to identify cancer genes , 2013, Bioinform..

[54]  Xl Li,et al.  miR-760 mediates chemoresistance through inhibition of epithelial mesenchymal transition in breast cancer cells. , 2016, European review for medical and pharmacological sciences.