Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
skip to main content
10.1145/2808719.2808763acmconferencesArticle/Chapter ViewAbstractPublication PagesbcbConference Proceedingsconference-collections
research-article

A systems biology approach for the identification of significantly perturbed genes

Published: 09 September 2015 Publication History

Abstract

Identifying the genes involved in the mechanisms differentiating two phenotypes is a crucial step in the analysis of high-throughput gene expression experiments. Although in the last decade several approaches have been developed in order to address this challenge, a number of important issues remain open. Even the most widely used approaches fail to incorporate information about known interactions among genes, and they often fail to yield reproducible results across similar experiments, both in terms of the set of genes and in terms of the mechanisms related to those genes. Here we propose a novel systems biology approach able to i) identify the genes that are involved in a biological mechanism relevant to the condition in analysis and ii) yield reproducible results across multiple data sets related to the same condition. This is achieved by using gene expression levels and existing knowledge about the interactions among genes. We apply our method on four data sets describing two conditions, and we compare our results with the results of the classical approach of identifying genes based on their differential expression and p-values. The results show that our approach is better at identifying genes that are involved in the mechanisms relevant to the phenotype in analysis, as well as producing more consistent results across data sets describing the same biological condition.

References

[1]
Gordon K Smyth. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Statistical Applications in Genetics and Molecular Biology, 3(1), 2004.
[2]
Sorin Drăghici, Purvesh Khatri, Aron C Eklund, and Zoltan Szallasi. Reliability and reproducibility issues in DNA microarray measurements. Trends in Genetics, 22(2):101--109, 2006.
[3]
Minoru Kanehisa, Michihiro Araki, Susumu Goto, Masahiro Hattori, Mika Hirakawa, Masumi Itoh, Toshiaki Katayama, Shuichi Kawashima, Shujiro Okuda, Toshiaki Tokimatsu, and Yoshihiro Yamanishi. KEGG for linking genomes to life and the environment. Nucleic Acids Research, 36(suppl 1):D480--D484, 2008.
[4]
Lukasz Salwinski, Christopher S Miller, Adam J Smith, Frank K Pettit, James U Bowie, and David Eisenberg. The database of interacting proteins: 2004 update. Nucleic acids research, 32(Suppl 1):D449--D451, 2004.
[5]
Trey Ideker, Owen Ozier, Benno Schwikowski, and Andrew F Siegel. Discovering regulatory and signalling circuits in molecular interaction networks. Bioinformatics, 18(suppl 1):S233--S240, 2002.
[6]
Dilip Rajagopalan and Pankaj Agarwal. Inferring pathways from gene lists using a literature-derived network of biological relationships. Bioinformatics, 21(6):788--793, 2005.
[7]
Lawrence Cabusora, Electra Sutton, Andy Fulmer, and Christian V Forst. Differential network expression during drug and stress response. Bioinformatics, 21(12):2898--2905, 2005.
[8]
Şerban Nacu, Rebecca Critchley-Thorne, Peter Lee, and Susan Holmes. Gene expression network analysis and applications to immunology. Bioinformatics, 23(7):850--858, 2007.
[9]
Igor Ulitsky, Richard M Karp, and Ron Shamir. Detecting disease-specific dysregulated pathways via analysis of clinical expression profiles. In Research in Computational Molecular Biology, pages 347--359. Springer, 2008.
[10]
Phuong Dao, Kendric Wang, Colin Collins, Martin Ester, Anna Lapuk, and S Cenk Sahinalp. Optimally discriminative subnetwork markers predict response to chemotherapy. Bioinformatics, 27(13):i205--i213, 2011.
[11]
Fabio Vandin, Eli Upfal, and Benjamin J Raphael. Algorithms for detecting significantly mutated pathways in cancer. Journal of Computational Biology, 18(3):507--522, 2011.
[12]
Christina Backes, Alexander Rurainski, Gunnar W Klau, Oliver Müller, Daniel Stöckel, Andreas Gerasch, Jan Küntzer, Daniela Maisel, Nicole Ludwig, Matthias Hein, Andreas Keller, Helmut Burtscher, Michael Kaufmann, Eckart Meese, and Hans-Peter Lenhof. An integer linear programming approach for finding deregulated subgraphs in regulatory networks. Nucleic acids research, 40(6):e43--e43, 2012.
[13]
Sorin Drăghici, Purvesh Khatri, Adi Laurentiu Tarca, Kashayp Amin, Arina Done, Călin Voichiţa, Constantin Georgescu, and Roberto Romero. A systems biology approach for pathway level analysis. Genome Research, 17(10):1537--1545, 2007.
[14]
Călin Voichiţa, Michele Donato, and Sorin Drǎghici. Incorporating gene significance in the impact analysis of signaling pathways. In Machine Learning and Applications (ICMLA), 2012 11th International Conference on, volume 1, pages 126--131, Boca Raton, FL, USA, 12--15 December 2012. IEEE.
[15]
Bradley Efron and Robert J Tibshirani. An introduction to the bootstrap. CRC press, 1994.
[16]
Michael Ashburner, Catherine A. Ball, Judith A. Blake, David Botstein, Heather Butler, J. Michael Cherry, Allan P. Davis, Kara Dolinski, Selina S. Dwight, Janan T. Eppig, Midori A. Harris, David P. Hill, Laurie Issel-Tarver, Andrew Kasarskis, Suzanna Lewis, John C. Matese, Joel E. Richardson, Martin Ringwald, Gerald M. Rubin, and Gavin Sherlock. Gene Ontology: tool for the unification of biology. Nature Genetics, 25:25--29, 2000.
[17]
Rafael A Irizarry, Bridget Hobbs, Francois Collin, Yasmin D Beazer-Barclay, Kristen J Antonellis, Uwe Scherf, and Terence P Speed. Exploration, Normalization, and Summaries of High Density Oligonucleotide Array Probe Level Data. Biostatistics, 4(2):249--264, 2003.
[18]
Yi Hong, Kok Sun Ho, Kong Weng Eu, and Peh Yean Cheah. A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: implication for tumorigenesis. Clinical Cancer Research, 13(4):1107--1114, 2007.
[19]
Orsolya Galamb, Balázs Györffy, Ferenc Sipos, Sándor Spisák, Anna Mária Németh, Pál Miheller, Zsolt Tulassay, Elek Dinya, and Béla Molnár. Inflammation, adenoma and cancer: objective classification of colon biopsy specimens with gene expression signature. Disease markers, 25(1):1--16, 2008.
[20]
Lisa M Coussens and Zena Werb. Inflammation and cancer. Nature, 420(6917):860--867, 2002.
[21]
Gordon W McLean, Neil O Carragher, Egle Avizienyte, Jeff Evans, Valerie G Brunton, and Margaret C Frame. The role of focal-adhesion kinase in cancer-a new therapeutic opportunity. Nature Reviews Cancer, 5(7):505--515, 2005.
[22]
Jim Tartaglia, Marie-Claude Bonnet, Neil Berinstein, Brian Barber, Michel Klein, and Philippe Moingeon. Therapeutic vaccines against melanoma and colorectal cancer. Vaccine, 19(17):2571--2575, 2001.
[23]
Martin J Rutkowski, Michael E Sughrue, Ari J Kane, Steven A Mills, and Andrew T Parsa. Cancer and the complement cascade. Molecular Cancer Research, 8(11):1453--1465, 2010.
[24]
Bryan T Hennessy, Debra L Smith, Prahlad T Ram, Yiling Lu, and Gordon B Mills. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature reviews Drug discovery, 4(12):988--1004, 2005.
[25]
Pengfei Lu, Valerie M Weaver, and Zena Werb. The extracellular matrix: a dynamic niche in cancer progression. The Journal of cell biology, 196(4):395--406, 2012.
[26]
Imad Shureiqi, Wei Jiang, Xiangsheng Zuo, Yuanqing Wu, Julie B Stimmel, Lisa M Leesnitzer, Jeffrey S Morris, Hui-Zhen Fan, Susan M Fischer, and Scott M Lippman. The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proceedings of the National Academy of Sciences, 100(17):9968--9973, 2003.
[27]
Stephan Brand, Julia Dambacher, Florian Beigel, Torsten Olszak, Joachim Diebold, Jan-Michel Otte, Burkhard Göke, and Sören T Eichhorst. CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Experimental cell research, 310(1):117--130, 2005.
[28]
Hua Xiong, Zhi-Gang Zhang, Xiao-Qing Tian, Dan-Feng Sun, Qin-Chuan Liang, Yan-Jie Zhang, Rong Lu, Ying-Xuan Chen, and Jing-Yuan Fang. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia, 10(3):287--297, 2008.
[29]
Stephan Brand, Torsten Olszak, Florian Beigel, Joachim Diebold, Jan-Michel Otte, Soeren T Eichhorst, Burkhard Göke, and Julia Dambacher. Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. Journal of cellular biochemistry, 97(4):709--723, 2006.
[30]
Alexandros Garouniatis, Adamantia Zizi-Sermpetzoglou, Spyros Rizos, Alkiviadis Kostakis, Nikolaos Nikiteas, and Athanasios G Papavassiliou. FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk. International journal of colorectal disease, 28(1):9--18, 2013.
[31]
Charles Bailey, Rupert Negus, Alistair Morris, Paul Ziprin, Robert Goldin, Paola Allavena, David Peck, and Ara Darzi. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clinical & experimental metastasis, 24(2):121--130, 2007.
[32]
Yan Sun, Shiyi Zhao, Hua Tian, Xiaoyun Xie, Faman Xiao, Kang Li, and Yugang Song. Depletion of PI3K p85alpha induces cell cycle arrest and apoptosis in colorectal cancer cells. Oncology reports, 22(6):1435--1441, 2009.
[33]
Karin Fransén, Maria Klintenäs, Anna Österström, Jan Dimberg, Hans-Jürg Monstein, and Peter Söderkvist. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis, 25(4):527--533, 2004.
[34]
Ulrik Lindforss, Henrik Zetterquist, Nikos Papadogiannakis, and Hans Olivecrona. Persistence of K-ras mutations in plasma after colorectal tumor resection. Anticancer research, 25(1B):657--661, 2005.
[35]
Andrea Sartore-Bianchi, Miriam Martini, Francesca Molinari, Silvio Veronese, Michele Nichelatti, Salvatore Artale, Federica Di Nicolantonio, Piercarlo Saletti, Sara De Dosso, Luca Mazzucchelli, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer research, 69(5):1851--1857, 2009.
[36]
Hyun-Ah Kim, Kwang-Ho Kim, and Ryung-Ah Lee. Expression of caveolin-1 is correlated with Akt-1 in colorectal cancer tissues. Experimental and molecular pathology, 80(2):165--170, 2006.
[37]
GF Nash, LF Turner, MF Scully, and AK Kakkar. Platelets and cancer. The lancet oncology, 3(7):425--430, 2002.
[38]
EL Wang, Zhi-Rong Qian, M Nakasono, T Tanahashi, K Yoshimoto, Y Bando, E Kudo, M Shimada, and Toshiaki Sano. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. British journal of cancer, 102(5):908--915, 2010.
[39]
Ruprecht Kuner, Thomas Muley, Michael Meister, Markus Ruschhaupt, Andreas Buness, Elizabeth C Xu, Phillipp Schnabel, Arne Warth, Annemarie Poustka, Holger Sültmann, et al. Global gene expression analysis reveals specific patterns of cell junctions in non-small cell lung cancer subtypes. Lung Cancer, 63(1):32--38, 2009.
[40]
Adi L Tarca, Mario Lauria, Michael Unger, Erhan Bilal, Stephanie Boue, Kushal Kumar Dey, Julia Hoeng, Heinz Koeppl, Florian Martin, Pablo Meyer, Preetam Nandy, Raquel Norel, Manuel Peitsch, Jeremy J Rice, Roberto Romero, Gustavo Stolovitzky, Marja Talikka, Yang Xiang, Christoph Zechner, and IMPROVER DSC Collaborators. Strengths and limitations of microarray-based phenotype prediction: lessons learned from the IMPROVER diagnostic signature challenge. Bioinformatics, 29(22):2892--2899, 2013.
[41]
E Brambilla, D Moro, D Veale, PY Brichon, P Stoebner, B Paramelle, and C Brambilla. Basal cell (basaloid) carcinoma of the lung: a new morphologic and phenotypic entity with separate prognostic significance. Human pathology, 23(9):993--1003, 1992.
[42]
Bin Zhao, Karen Tumaneng, and Kun-Liang Guan. The hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature cell biology, 13(8):877--883, 2011.
[43]
Jun Hou, Joachim Aerts, Bianca Den Hamer, Wilfred Van Ijcken, Michael Den Bakker, Peter Riegman, Cor van der Leest, Peter van der Spek, John A Foekens, Henk C Hoogsteden, Frank Grosveld, and Sjaak Philipsen. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One, 5(4):e10312, 2010.
[44]
Huachuan Zheng, Hiroshi Saito, Shinji Masuda, Xianghong Yang, and Yasuo Takano. Phosphorylated GSK3β-ser9 and EGFR are good prognostic factors for lung carcinomas. Anticancer research, 27(5B):3561--3569, 2007.
[45]
Don X Nguyen, Anne C Chiang, Xiang H-F Zhang, Juliet Y Kim, Mark G Kris, Marc Ladanyi, William L Gerald, and Joan Massagué. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell, 138(1):51--62, 2009.
[46]
Kazutsugu Uematsu, Biao He, Liang You, Zhidong Xu, Frank McCormick, and David Mark Jablons. Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene, 22(46):7218--7221, 2003.
[47]
Shinichiro Kase, Kenji Sugio, Koji Yamazaki, Tatsuro Okamoto, Tokujiro Yano, and Keizo Sugimachi. Expression of E-cadherin and β-catenin in human non-small cell lung cancer and the clinical significance. Clinical Cancer Research, 6(12):4789--4796, 2000.
[48]
Hong-Tao Xu, Liang Wang, Dong Lin, Yang Liu, Nan Liu, Xi-Ming Yuan, and En-Hua Wang. Abnormal β-Catenin and Reduced Axin Expression Are Associated With Poor Differentiation and Progression in Non--Small Cell Lung Cancer. American journal of clinical pathology, 125(4):534--541, 2006.
[49]
Venkateshwar G Keshamouni, Raju C Reddy, Douglas A Arenberg, Binju Joel, Victor J Thannickal, Gregory P Kalemkerian, and Theodore J Standiford. Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene, 23(1):100--108, 2004.
[50]
PJ Roberts and CJ Der. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26(22):3291--3310, 2007.
[51]
Sunil Singhal, Anil Vachani, Danielle Antin-Ozerkis, Larry R Kaiser, and Steven M Albelda. Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non-small cell lung cancer: a review. Clinical Cancer Research, 11(11):3974--3986, 2005.
[52]
Il Lae Jung, Hyo Jin Kang, Kug Chan Kim, and In Gyu Kim. PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer. International journal of molecular medicine, 25(4):517--523, 2010.
[53]
Charles M Rudin, Steffen Durinck, Eric W Stawiski, John T Poirier, Zora Modrusan, David S Shames, Emily A Bergbower, Yinghui Guan, James Shin, Joseph Guillory, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics, 44(10):1111--1116, 2012.
[54]
Wei-Peng Zhao, Bo Zhu, Yu-Zhong Duan, and Zheng-Tang Chen. Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells. Oncology reports, 21(6):1405--1411, 2009.
[55]
An Na Kim, Woo-Kwang Jeon, Kyu-Hyoung Lim, Hui-Young Lee, Woo Jin Kim, and Byung-Chul Kim. Fyn mediates transforming growth factor-beta1-induced down-regulation of E-cadherin in human A549 lung cancer cells. Biochemical and biophysical research communications, 407(1):181--184, 2011.
[56]
J Lin, T Sun, L Ji, W Deng, J Roth, J Minna, and R Arlinghaus. Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1. Oncogene, 26(49):6989--6996, 2007.
[57]
Hong Lei Chen, Li Fang Fan, Jun Gao, Jing Ping Ouyang, and Yu Xia Zhang. Differential expression and function of the caveolin-1 gene in non-small cell lung carcinoma. Oncology reports, 25(2):359--366, 2011.

Cited By

View all
  • (2024)Ant colony optimization for the identification of dysregulated gene subnetworks from expression dataBMC Bioinformatics10.1186/s12859-024-05871-x25:1Online publication date: 1-Aug-2024
  • (2019)A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene SignaturesFrontiers in Genetics10.3389/fgene.2019.0015910Online publication date: 19-Mar-2019
  • (2019)GeneSurrounder: network-based identification of disease genes in expression dataBMC Bioinformatics10.1186/s12859-019-2829-y20:1Online publication date: 6-May-2019
  • Show More Cited By

Index Terms

  1. A systems biology approach for the identification of significantly perturbed genes

    Recommendations

    Comments

    Information & Contributors

    Information

    Published In

    cover image ACM Conferences
    BCB '15: Proceedings of the 6th ACM Conference on Bioinformatics, Computational Biology and Health Informatics
    September 2015
    683 pages
    ISBN:9781450338530
    DOI:10.1145/2808719
    Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected]

    Sponsors

    Publisher

    Association for Computing Machinery

    New York, NY, United States

    Publication History

    Published: 09 September 2015

    Permissions

    Request permissions for this article.

    Check for updates

    Author Tags

    1. differentiating phenotypes
    2. perturbed genes

    Qualifiers

    • Research-article

    Conference

    BCB '15
    Sponsor:

    Acceptance Rates

    BCB '15 Paper Acceptance Rate 48 of 141 submissions, 34%;
    Overall Acceptance Rate 254 of 885 submissions, 29%

    Contributors

    Other Metrics

    Bibliometrics & Citations

    Bibliometrics

    Article Metrics

    • Downloads (Last 12 months)0
    • Downloads (Last 6 weeks)0
    Reflects downloads up to 01 Jan 2025

    Other Metrics

    Citations

    Cited By

    View all
    • (2024)Ant colony optimization for the identification of dysregulated gene subnetworks from expression dataBMC Bioinformatics10.1186/s12859-024-05871-x25:1Online publication date: 1-Aug-2024
    • (2019)A Multi-Cohort and Multi-Omics Meta-Analysis Framework to Identify Network-Based Gene SignaturesFrontiers in Genetics10.3389/fgene.2019.0015910Online publication date: 19-Mar-2019
    • (2019)GeneSurrounder: network-based identification of disease genes in expression dataBMC Bioinformatics10.1186/s12859-019-2829-y20:1Online publication date: 6-May-2019
    • (2019)GSMA: an approach to identify robust global and test Gene Signatures using Meta-AnalysisBioinformatics10.1093/bioinformatics/btz56136:2(487-495)Online publication date: 22-Jul-2019
    • (2017)Signaling pathway impact analysis by incorporating the importance and specificity of genes (SPIA-IS)Computational Biology and Chemistry10.1016/j.compbiolchem.2017.09.00971:C(236-244)Online publication date: 1-Dec-2017

    View Options

    Login options

    View options

    PDF

    View or Download as a PDF file.

    PDF

    eReader

    View online with eReader.

    eReader

    Media

    Figures

    Other

    Tables

    Share

    Share

    Share this Publication link

    Share on social media