Inference of Cancer-specific Gene Regulatory Networks Using Soft Computing Rules

Perturbations of gene regulatory networks are essentially responsible for oncogenesis. Therefore, inferring the gene regulatory networks is a key step to overcoming cancer. In this work, we propose a method for inferring directed gene regulatory networks based on soft computing rules, which can identify important cause-effect regulatory relations of gene expression. First, we identify important genes associated with a specific cancer (colon cancer) using a supervised learning approach. Next, we reconstruct the gene regulatory networks by inferring the regulatory relations among the identified genes, and their regulated relations by other genes within the genome. We obtain two meaningful findings. One is that upregulated genes are regulated by more genes than downregulated ones, while downregulated genes regulate more genes than upregulated ones. The other one is that tumor suppressors suppress tumor activators and activate other tumor suppressors strongly, while tumor activators activate other tumor activators and suppress tumor suppressors weakly, indicating the robustness of biological systems. These findings provide valuable insights into the pathogenesis of cancer.

[1]  J. Downward Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[2]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[3]  F. Bruggeman,et al.  Cancer: a Systems Biology disease. , 2006, Bio Systems.

[4]  S. Shen-Orr,et al.  Networks Network Motifs : Simple Building Blocks of Complex , 2002 .

[5]  H. Hirai,et al.  Activation mechanism of the N-ras oncogene in human leukemias detected by synthetic oligonucleotide probes. , 1987, Biochemical and biophysical research communications.

[6]  Illinois.,et al.  Cancer Genetics , 1976, British Journal of Cancer.

[7]  J. Stelling,et al.  Robustness of Cellular Functions , 2004, Cell.

[8]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[9]  Alberto de la Fuente,et al.  Discovery of meaningful associations in genomic data using partial correlation coefficients , 2004, Bioinform..

[10]  Patrik D'haeseleer,et al.  Linear Modeling of mRNA Expression Levels During CNS Development and Injury , 1998, Pacific Symposium on Biocomputing.

[11]  J. Hasty,et al.  Reverse engineering gene networks: Integrating genetic perturbations with dynamical modeling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Sherr,et al.  Principles of Tumor Suppression , 2004, Cell.

[13]  E. Reddy,et al.  Mechanism of activation of an N-ras oncogene of SW-1271 human lung carcinoma cells. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[15]  H. Kitano,et al.  In Vivo Robustness Analysis of Cell Division Cycle Genes in Saccharomyces cerevisiae , 2006, PLoS genetics.

[16]  Aniruddha Datta,et al.  External Control in Markovian Genetic Regulatory Networks , 2004, Machine Learning.

[17]  U. Alon,et al.  Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Stephen H. Friend,et al.  A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma , 1986, Nature.

[19]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[20]  Ronald W. Davis,et al.  Role of duplicate genes in genetic robustness against null mutations , 2003, Nature.

[21]  Satoru Miyano,et al.  Identification of gene regulatory networks by strategic gene disruptions and gene overexpressions , 1998, SODA '98.

[22]  P. R. ten Wolde,et al.  DNA looping provides stability and robustness to the bacteriophage λ switch , 2009, Proceedings of the National Academy of Sciences.

[23]  Cori Bargmann,et al.  Mechanism of activation of a human oncogene , 1982, Nature.

[24]  R Hofestädt,et al.  Interactive modelling and simulation of biochemical networks. , 1995, Computers in biology and medicine.

[25]  Akutsu,et al.  A System for Identifying Genetic Networks from Gene Expression Patterns Produced by Gene Disruptions and Overexpressions. , 1998, Genome informatics. Workshop on Genome Informatics.

[26]  E. Fearon Human cancer syndromes: clues to the origin and nature of cancer. , 1997, Science.

[27]  Z. Pawlak Rough Sets: Theoretical Aspects of Reasoning about Data , 1991 .

[28]  Bruce A.J. Ponder,et al.  Cancer genetics , 2001, Nature.

[29]  Q. Cui,et al.  Regulatory network motifs and hotspots of cancer genes in a mammalian cellular signalling network. , 2007, IET systems biology.

[30]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Andreas Wagner,et al.  Duplicate genes and robustness to transient gene knock-downs in Caenorhabditis elegans , 2004, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[32]  D. Marsh,et al.  Genetic insights into familial cancers-- update and recent discoveries. , 2002, Cancer letters.

[33]  Paul A. Bates,et al.  Global topological features of cancer proteins in the human interactome , 2006, Bioinform..

[34]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[35]  Timothy S Gardner,et al.  Reverse-engineering transcription control networks. , 2005, Physics of life reviews.

[36]  Ian H. Witten,et al.  Data mining: practical machine learning tools and techniques, 3rd Edition , 1999 .

[37]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[38]  R Hofestädt,et al.  Quantitative modeling of biochemical networks , 1998, Silico Biol..

[39]  D. Ledbetter,et al.  Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. , 1989, Science.

[40]  Usama M. Fayyad,et al.  Multi-Interval Discretization of Continuous-Valued Attributes for Classification Learning , 1993, IJCAI.

[41]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[42]  Shinichiro Wachi,et al.  Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues , 2005, Bioinform..

[43]  Satoru Miyano,et al.  Identification of Genetic Networks from a Small Number of Gene Expression Patterns Under the Boolean Network Model , 1998, Pacific Symposium on Biocomputing.

[44]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[45]  Richard Bonneau,et al.  The Inferelator: an algorithm for learning parsimonious regulatory networks from systems-biology data sets de novo , 2006, Genome Biology.

[46]  Xiaobo Zhou,et al.  A Bayesian connectivity-based approach to constructing probabilistic gene regulatory networks , 2004, Bioinform..

[47]  D. di Bernardo,et al.  How to infer gene networks from expression profiles , 2007, Molecular systems biology.

[48]  J. Collins,et al.  Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks , 2005, Nature Biotechnology.

[49]  J. Collins,et al.  A network biology approach to prostate cancer , 2007, Molecular systems biology.

[50]  Albert-László Barabási,et al.  Statistical mechanics of complex networks , 2001, ArXiv.

[51]  Satoru Miyano,et al.  Inferring qualitative relations in genetic networks and metabolic pathways , 2000, Bioinform..

[52]  Adam A. Margolin,et al.  Reverse engineering of regulatory networks in human B cells , 2005, Nature Genetics.

[53]  Paul A. Bates,et al.  Cluster analysis of networks generated through homology: automatic identification of important protein communities involved in cancer metastasis , 2006, BMC Bioinformatics.

[54]  P. Leder,et al.  Translocations among antibody genes in human cancer. , 1983, Science.

[55]  E. Wang,et al.  Genetic studies of diseases , 2007, Cellular and Molecular Life Sciences.

[56]  H. Kitano Towards a theory of biological robustness , 2007, Molecular systems biology.

[57]  Xiaosheng Wang,et al.  Microarray-Based Cancer Prediction Using Soft Computing Approach , 2009, Cancer informatics.

[58]  H. Kitano,et al.  Robustness trade-offs and host–microbial symbiosis in the immune system , 2006, Molecular systems biology.

[59]  M. Barbacid,et al.  Mechanism of activation of the human trk oncogene. , 1989, Molecular and cellular biology.

[60]  H. Kitano Systems Biology: A Brief Overview , 2002, Science.

[61]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[62]  Andrew J. Bulpitt,et al.  A Primer on Learning in Bayesian Networks for Computational Biology , 2007, PLoS Comput. Biol..

[63]  D. Vitkup,et al.  Role of Duplicate Genes in Robustness against Deleterious Human Mutations , 2008, PLoS genetics.

[64]  Yadong Wang,et al.  Constructing disease-specific gene networks using pair-wise relevance metric: Application to colon cancer identifies interleukin 8, desmin and enolase 1 as the central elements , 2008, BMC Systems Biology.

[65]  Paul P. Wang,et al.  Advances to Bayesian network inference for generating causal networks from observational biological data , 2004, Bioinform..

[66]  Michal Linial,et al.  Using Bayesian Networks to Analyze Expression Data , 2000, J. Comput. Biol..

[67]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[68]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[69]  Martin Kuiper,et al.  BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks , 2005, Bioinform..

[70]  Chris Wiggins,et al.  ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context , 2004, BMC Bioinformatics.

[71]  I S Kohane,et al.  Mutual information relevance networks: functional genomic clustering using pairwise entropy measurements. , 1999, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[72]  P. Laird,et al.  Adenocarcinoma Epigenetic Patterns in the Progression of Esophageal Updated Version , 2001 .

[73]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[74]  A. Brazma,et al.  Towards reconstruction of gene networks from expression data by supervised learning , 2003, Genome Biology.

[75]  J. Collins,et al.  Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling , 2003, Science.

[76]  Diego di Bernardo,et al.  Inference of gene regulatory networks and compound mode of action from time course gene expression profiles , 2006, Bioinform..

[77]  Marcel J. T. Reinders,et al.  Least absolute regression network analysis of the murine osteoblast differentiation network , 2006, Bioinform..

[78]  D. Pe’er,et al.  Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data , 2003, Nature Genetics.

[79]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[80]  Ralf Hofestädt,et al.  Grammatical Formalization of Metabolic Processes , 1993, ISMB.