title: Prediction and testing of biological networks underlying intestinal cancer.
abstract: Colorectal cancer progresses through an accumulation of somatic mutations, some of which reside in so-called "driver" genes that provide a growth advantage to the tumor. To identify points of intersection between driver gene pathways, we implemented a network analysis framework using protein interactions to predict likely connections--both precedented and novel--between key driver genes in cancer. We applied the framework to find significant connections between two genes, Apc and Cdkn1a (p21), known to be synergistic in tumorigenesis in mouse models. We then assessed the functional coherence of the resulting Apc-Cdkn1a network by engineering in vivo single node perturbations of the network: mouse models mutated individually at Apc (Apc(1638N+/-)) or Cdkn1a (Cdkn1a(-/-)), followed by measurements of protein and gene expression changes in intestinal epithelial tissue. We hypothesized that if the predicted network is biologically coherent (functional), then the predicted nodes should associate more specifically with dysregulated genes and proteins than stochastically selected genes and proteins. The predicted Apc-Cdkn1a network was significantly perturbed at the mRNA-level by both single gene knockouts, and the predictions were also strongly supported based on physical proximity and mRNA coexpression of proteomic targets. These results support the functional coherence of the proposed Apc-Cdkn1a network and also demonstrate how network-based predictions can be statistically tested using high-throughput biological data.
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Vishal N
authors.initials: VN
authors.lastname: Patel
authors.forename: Gurkan
authors.initials: G
authors.lastname: Bebek
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: Donghai
authors.initials: D
authors.lastname: Wang
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21
references.citation: Oncogene. 2005 Nov 3;24(48):7203-12
references.pmid: 16170380
references.citation: Am J Physiol Renal Physiol. 2008 Jul;295(1):F145-52
references.pmid: 18434386
references.citation: Oncogene. 2008 Oct 23;27(49):6365-75
references.pmid: 18679417
references.citation: Oncogene. 2005 Mar 10;24(11):1847-59
references.pmid: 15688028
references.citation: Nat Med. 2004 Aug;10(8):789-99
references.pmid: 15286780
references.citation: BMC Bioinformatics. 2007 Sep 13;8:335
references.pmid: 17854489
references.citation: Int J Oncol. 2009 May;34(5):1181-9
references.pmid: 19360331
references.citation: Mol Syst Biol. 2007;3:140
references.pmid: 17940530
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D885-90
references.pmid: 18940857
references.citation: Am J Physiol Cell Physiol. 2009 Oct;297(4):C935-44
references.pmid: 19625610
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
references.pmid: 18077471
references.citation: PLoS Comput Biol. 2010 Jan 15;6(1):e1000639
references.pmid: 20090827
references.citation: Oncogene. 2007 Jan 11;26(2):312-20
references.pmid: 16819509
references.citation: Cancer Res. 2003 Oct 15;63(20):6894-9
references.pmid: 14583488
references.citation: Int J Cancer. 2000 Jan 20;89(1):14-8
references.pmid: 10719725
references.citation: Nat Genet. 2008 Dec;40(12):1436-44
references.pmid: 19011632
references.citation: Gastroenterology. 2009 May;136(5):1680-8.e7
references.pmid: 19208363
references.citation: J Cell Physiol. 2008 Nov;217(2):423-32
references.pmid: 18543249
references.citation: FEBS J. 2008 Jun;275(12):3099-109
references.pmid: 18479465
references.citation: J Cell Sci. 2008 May 15;121(Pt 10):1758-69
references.pmid: 18445683
references.citation: J Cell Biochem. 2005 Jan 1;94(1):178-93
references.pmid: 15526283
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Bioinformatics. 2006 Oct 1;22(19):2373-80
references.pmid: 16877751
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Physiol Genomics. 2003 Nov 11;15(3):228-35
references.pmid: 13130079
references.citation: Nucleic Acids Res. 1999 Jan 1;27(1):44-8
references.pmid: 9847138
references.citation: J Exp Med. 2006 Dec 25;203(13):2895-906
references.pmid: 17178917
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
references.pmid: 17090670
references.citation: Mol Cell Proteomics. 2009 Apr;8(4):827-45
references.pmid: 19098285
references.citation: Cancer Res. 2001 Jan 15;61(2):565-9
references.pmid: 11212250
references.citation: Cancer Res. 2006 Sep 1;66(17):8633-9
references.pmid: 16951177
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D561-5
references.pmid: 17145710
references.citation: Br J Cancer. 1999 Jan;79(1):59-64
references.pmid: 10408694
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Mol Cell Biol. 2008 Oct;28(20):6462-72
references.pmid: 18710949
references.citation: Cancer Res. 2004 Sep 1;64(17):6035-40
references.pmid: 15342384
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D281-8
references.pmid: 18039703
references.citation: Curr Biol. 1996 Nov 1;6(11):1435-44
references.pmid: 8939605
references.citation: J Proteomics. 2008 Dec 2;71(5):530-46
references.pmid: 18824147
references.citation: J Biol Chem. 1973 Apr 10;248(7):2536-41
references.pmid: 4698230
references.citation: Bioinformatics. 2007 Apr 15;23(8):980-7
references.pmid: 17303618
references.citation: Clin Cancer Res. 2008 Dec 1;14(23):7843-9
references.pmid: 19047113
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D411-4
references.pmid: 16381900
references.citation: Nat Cell Biol. 2001 Apr;3(4):433-8
references.pmid: 11283620
references.citation: Genetics. 2008 Sep;180(1):601-9
references.pmid: 18723878
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):6959-64
references.pmid: 18474861
references.citation: Proteomics. 2009 Sep;9(18):4276-83
references.pmid: 19662629
references.citation: Carcinogenesis. 2008 Jul;29(7):1435-40
references.pmid: 18550571
references.citation: Science. 2007 Nov 16;318(5853):1108-13
references.pmid: 17932254
references.citation: Mol Carcinog. 2009 Feb;48(2):156-66
references.pmid: 18613032
references.citation: Int J Cancer. 2009 Jan 1;124(1):68-74
references.pmid: 18924133
references.citation: Drug Metab Dispos. 2006 Mar;34(3):495-503
references.pmid: 16381662
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D637-40
references.pmid: 18000002