title: Elucidating the altered transcriptional programs in breast cancer using independent component analysis.
abstract: The quantity of mRNA transcripts in a cell is determined by a complex interplay of cooperative and counteracting biological processes. Independent Component Analysis (ICA) is one of a few number of unsupervised algorithms that have been applied to microarray gene expression data in an attempt to understand phenotype differences in terms of changes in the activation/inhibition patterns of biological pathways. While the ICA model has been shown to outperform other linear representations of the data such as Principal Components Analysis (PCA), a validation using explicit pathway and regulatory element information has not yet been performed. We apply a range of popular ICA algorithms to six of the largest microarray cancer datasets and use pathway-knowledge and regulatory-element databases for validation. We show that ICA outperforms PCA and clustering-based methods in that ICA components map closer to known cancer-related pathways, regulatory modules, and cancer phenotypes. Furthermore, we identify cancer signalling and oncogenic pathways and regulatory modules that play a prominent role in breast cancer and relate the differential activation patterns of these to breast cancer phenotypes. Importantly, we find novel associations linking immune response and epithelial-mesenchymal transition pathways with estrogen receptor status and histological grade, respectively. In addition, we find associations linking the activity levels of biological pathways and transcription factors (NF1 and NFAT) with clinical outcome in breast cancer. ICA provides a framework for a more biologically relevant interpretation of genomewide transcriptomic data. Adopting ICA as the analysis tool of choice will help understand the phenotype-pathway relationship and thus help elucidate the molecular taxonomy of heterogeneous cancers and of other complex genetic diseases.
authors: Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk
authors: Andrew E
authors: AE
authors: Teschendorff
authors: Michel
authors: M
authors: Journée
authors: Pierre A
authors: PA
authors: Absil
authors: Rodolphe
authors: R
authors: Sepulchre
authors: Carlos
authors: C
authors: Caldas
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins
references: Mol Biol Rep. 1999 Dec;26(4):223-30
references: 10634504
references: Oncogene. 2007 Mar 1;26(10):1507-16
references: 16936776
references: Nature. 2000 Aug 17;406(6797):747-52
references: 10963602
references: Bioinformatics. 2002 Jan;18(1):51-60
references: 11836211
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12963-8
references: 12297621
references: Bioinformatics. 2002 Dec;18(12):1617-24
references: 12490446
references: N Engl J Med. 2002 Dec 19;347(25):1999-2009
references: 12490681
references: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3351-6
references: 12631705
references: Mol Biol Cell. 2003 Aug;14(8):3208-15
references: 12925757
references: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8
references: 12917485
references: Oncogene. 2003 Oct 16;22(46):7155-69
references: 14562044
references: Genome Biol. 2003;4(11):R76
references: 14611662
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13418-23
references: 14593198
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15522-7
references: 14673099
references: Comput Biol Chem. 2004 Feb;28(1):3-10
references: 15022635
references: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9309-14
references: 15184677
references: Oncogene. 2004 Aug 26;23(39):6677-83
references: 15247901
references: Nat Genet. 2004 Oct;36(10):1090-8
references: 15448693
references: Oncogene. 2004 Oct 28;23(50):8238-46
references: 15378019
references: Adv Immunol. 1997;64:65-104
references: 9100980
references: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references: 9843981
references: Neural Comput. 1999 Jan 1;11(1):157-92
references: 9950728
references: Oncogene. 2004 Nov 18;23(54):8743-55
references: 15467738
references: Br J Cancer. 2004 Nov 29;91(11):1924-30
references: 15558074
references: J Comput Biol. 2004;11(6):1090-109
references: 15662200
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Oncogene. 2007 Sep 27;26(44):6420-30
references: 17452973
references: Lancet. 2005 Feb 19-25;365(9460):671-9
references: 15721472
references: Nature. 2005 Mar 17;434(7031):338-45
references: 15735639
references: Nat Genet. 2005 Jun;37(6):579-83
references: 15920519
references: Bioinformatics. 2005 Jul 1;21(13):3025-33
references: 15860564
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Eur J Hum Genet. 2005 Dec;13(12):1303-11
references: 16205741
references: Mol Cell. 2005 Nov 23;20(4):539-50
references: 16307918
references: Int J Oncol. 2006 Jan;28(1):67-76
references: 16327981
references: Nature. 2006 Jan 19;439(7074):353-7
references: 16273092
references: J Natl Cancer Inst. 2006 Feb 15;98(4):262-72
references: 16478745
references: Eur J Cancer. 2006 Mar;42(4):485-91
references: 16380248
references: Oncogene. 2006 Apr 6;25(15):2273-84
references: 16288205
references: BMC Bioinformatics. 2006;7:175
references: 16569230
references: J Biol Chem. 2006 May 5;281(18):12210-7
references: 16505480
references: N Engl J Med. 2006 Jun 8;354(23):2419-30
references: 16760442
references: Arch Immunol Ther Exp (Warsz). 2006 May-Jun;54(3):149-63
references: 16652219
references: Mol Cell Biol. 2006 Aug;26(16):6024-36
references: 16880514
references: Bioinformatics. 2006 Aug 1;22(15):1855-62
references: 16709589
references: BMC Bioinformatics. 2006;7:290
references: 16762055
references: Clin Cancer Res. 2006 Oct 1;12(19):5641-7
references: 17000652
references: Oncogene. 2006 Oct 30;25(51):6758-80
references: 17072327
references: Mol Cancer. 2006;5(1):55
references: 17081305
references: Nat Genet. 2006 Dec;38(12):1386-96
references: 17099711
references: Nat Genet. 2007 Jan;39(1):41-51
references: 17173048
references: Genome Biol. 2006;7(10):R93
references: 17044931
references: Genome Biol. 2006;7(10):R101
references: 17076897
references: J Med Genet. 2007 Aug;44(8):481-4
references: 17369502