LNDriver: identifying driver genes by integrating mutation and expression data based on gene-gene interaction network

BackgroundCancer is a complex disease which is characterized by the accumulation of genetic alterations during the patient’s lifetime. With the development of the next-generation sequencing technology, multiple omics data, such as cancer genomic, epigenomic and transcriptomic data etc., can be measured from each individual. Correspondingly, one of the key challenges is to pinpoint functional driver mutations or pathways, which contributes to tumorigenesis, from millions of functional neutral passenger mutations.ResultsIn this paper, in order to identify driver genes effectively, we applied a generalized additive model to mutation profiles to filter genes with long length and constructed a new gene-gene interaction network. Then we integrated the mutation data and expression data into the gene-gene interaction network. Lastly, greedy algorithm was used to prioritize candidate driver genes from the integrated data. We named the proposed method Length-Net-Driver (LNDriver).ConclusionsExperiments on three TCGA datasets, i.e., head and neck squamous cell carcinoma, kidney renal clear cell carcinoma and thyroid carcinoma, demonstrated that the proposed method was effective. Also, it can identify not only frequently mutated drivers, but also rare candidate driver genes.

[1]  Yuan Ren,et al.  SHP2E76K mutant promotes lung tumorigenesis in transgenic mice. , 2014, Carcinogenesis.

[2]  Giovanni Tesoriere,et al.  RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis , 2013, Journal of cellular physiology.

[3]  K. Rauen,et al.  The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. , 2009, Current opinion in genetics & development.

[4]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[5]  D. Goodrich,et al.  RB1, development, and cancer. , 2011, Current topics in developmental biology.

[6]  R. Gibbs,et al.  Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 , 2011, Science.

[7]  Yoh Iwasa,et al.  An Evolutionary Approach for Identifying Driver Mutations in Colorectal Cancer , 2015, PLoS Comput. Biol..

[8]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of head and neck squamous cell carcinomas , 2015, Nature.

[9]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[10]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[11]  Michael B. Stadler,et al.  Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases , 2014, Oncogene.

[12]  Makoto Nishio,et al.  Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer , 2014, Cancer medicine.

[13]  Kyusam Choi,et al.  The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas , 2012, Modern Pathology.

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

[15]  Simon C. K. Shiu,et al.  Molecular Pattern Discovery Based on Penalized Matrix Decomposition , 2011, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

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

[17]  Gary D Bader,et al.  International network of cancer genome projects , 2010, Nature.

[18]  Matthew B. Callaway,et al.  MuSiC: Identifying mutational significance in cancer genomes , 2012, Genome research.

[19]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[20]  Zhongming Zhao,et al.  Advances in computational approaches for prioritizing driver mutations and significantly mutated genes in cancer genomes , 2016, Briefings Bioinform..

[21]  S. Nelson,et al.  Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation , 2010, Nature.

[22]  Shi-Hua Zhang,et al.  Efficient methods for identifying mutated driver pathways in cancer , 2012, Bioinform..

[23]  P. Ladenson,et al.  BRAF mutation in papillary thyroid carcinoma. , 2003, Journal of the National Cancer Institute.

[24]  Desmond J. Higham,et al.  GeneRank: Using search engine technology for the analysis of microarray experiments , 2005, BMC Bioinformatics.

[25]  Khee Chee Soo,et al.  Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma , 2008, Genes, chromosomes & cancer.

[26]  Peilin Jia,et al.  VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data , 2014, PLoS Comput. Biol..

[27]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[28]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[29]  A. Sivachenko,et al.  Sequence analysis of mutations and translocations across breast cancer subtypes , 2012, Nature.

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

[31]  Q. Gao,et al.  Expression and clinical significance of tyrosine phosphatase SHP2 in thyroid carcinoma. , 2015, Oncology letters.

[32]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[33]  A. D. Dei Tos,et al.  Soft tissue tumors associated with EWSR1 translocation , 2010, Virchows Archiv.

[34]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[35]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[36]  Setia Pramana,et al.  Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival , 2015, Bioinform..

[37]  Simon C. K. Shiu,et al.  Metasample-Based Sparse Representation for Tumor Classification , 2011, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[38]  Shi-Hua Zhang,et al.  Identification of mutated core cancer modules by integrating somatic mutation, copy number variation, and gene expression data , 2013, BMC Systems Biology.

[39]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[40]  M. Frame,et al.  Src in cancer: deregulation and consequences for cell behaviour. , 2002, Biochimica et biophysica acta.