title: Genes with relevance for early to late progression of colon carcinoma based on combined genomic and transcriptomic information from the same patients.
abstract: BACKGROUND
  Genetic and epigenetic alterations in colorectal cancer are numerous. However, it is difficult to judge whether such changes are primary or secondary to the appearance and progression of tumors. Therefore, the aim of the present study was to identify altered DNA regions with significant covariation to transcription alterations along colon cancer progression.
  
  
  METHODS
  Tumor and normal colon tissue were obtained at primary operations from 24 patients selected by chance. DNA, RNA and microRNAs were extracted from the same biopsy material in all individuals and analyzed by oligo-nucleotide array-based comparative genomic hybridization (CGH), mRNA- and microRNA oligo-arrays. Statistical analyses were performed to assess statistical interactions (correlations, co-variations) between DNA copy number changes and significant alterations in gene and microRNA expression using appropriate parametric and non-parametric statistics.
  
  
  RESULTS
  Main DNA alterations were located on chromosome 7, 8, 13 and 20. Tumor DNA copy number gain increased with tumor progression, significantly related to increased gene expression. Copy number loss was not observed in Dukes A tumors. There was no significant relationship between expressed genes and tumor progression across Dukes A-D tumors; and no relationship between tumor stage and the number of microRNAs with significantly altered expression. Interaction analyses identified overall 41 genes, which discriminated early Dukes A plus B tumors from late Dukes C plus D tumor; 28 of these genes remained with correlations between genomic and transcriptomic alterations in Dukes C plus D tumors and 17 in Dukes D. One microRNA (microR-663) showed interactions with DNA alterations in all Dukes A-D tumors.
  
  
  CONCLUSIONS
  Our modeling confirms that colon cancer progression is related to genomic instability and altered gene expression. However, early invasive tumor growth seemed rather related to transcriptomic alterations, where changes in microRNA may be an early phenomenon, and less to DNA copy number changes.
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Lagerstedt
authors.forename: Erik
authors.initials: E
authors.lastname: Kristiansson
authors.forename: Christina
authors.initials: C
authors.lastname: Lönnroth
authors.forename: Marianne
authors.initials: M
authors.lastname: Andersson
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Iresjö
authors.forename: Annika
authors.initials: A
authors.lastname: Gustafsson
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hansson
authors.forename: Ulf
authors.initials: U
authors.lastname: Kressner
authors.forename: Svante
authors.initials: S
authors.lastname: Nordgren
authors.forename: Fredrik
authors.initials: F
authors.lastname: Enlund
authors.forename: Kent
authors.initials: K
authors.lastname: Lundholm
references.citation: Comput Biol Chem. 2009 Feb;33(1):94-9
references.pmid: 18723399
references.citation: Cancer Res. 2005 Nov 1;65(21):9603-6
references.pmid: 16266975
references.citation: BMC Syst Biol. 2008 Aug 10;2:72
references.pmid: 18691435
references.citation: Cell Res. 2008 Aug;18(8):823-33
references.pmid: 18607389
references.citation: Oncogene. 2004 Feb 19;23(7):1377-91
references.pmid: 14973550
references.citation: World J Surg. 2009 Apr;33(4):638-46
references.pmid: 19123024
references.citation: Nat Genet. 2009 Feb;41(2):178-186
references.pmid: 19151715
references.citation: Nucleic Acids Res. 2002 Feb 15;30(4):e15
references.pmid: 11842121
references.citation: BMC Genomics. 2005 May 10;6:69
references.pmid: 15882471
references.citation: BMC Cancer. 2006 Jul 12;6:186
references.pmid: 16836752
references.citation: JAMA. 2008 Jan 30;299(4):425-36
references.pmid: 18230780
references.citation: Cancer Res. 2008 Mar 1;68(5):1284-95
references.pmid: 18316590
references.citation: Cancer Lett. 2003 Feb 20;190(2):125-33
references.pmid: 12565166
references.citation: Leuk Lymphoma. 2007 Aug;48(8):1618-27
references.pmid: 17701594
references.citation: Cell Cycle. 2009 Feb 1;8(3):383-90
references.pmid: 19177016
references.citation: Cancer Res. 2004 Aug 15;64(16):5556-9
references.pmid: 15313890
references.citation: Am J Pathol. 2009 Feb;174(2):371-9
references.pmid: 19147813
references.citation: Mol Cancer Res. 2008 Apr;6(4):592-603
references.pmid: 18403638
references.citation: Breast Cancer Res. 2008;10(2):203
references.pmid: 18373886
references.citation: Genes Chromosomes Cancer. 2007 Jan;46(1):10-26
references.pmid: 17044061
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9067-72
references.pmid: 15199222
references.citation: Int J Oncol. 2009 Apr;34(4):1069-75
references.pmid: 19287964
references.citation: Cancer Biol Ther. 2008 Mar;7(3):387-91
references.pmid: 18717013
references.citation: Mol Cancer. 2006 Jul 19;5:29
references.pmid: 16854228
references.citation: BMC Med Genet. 2008 Jul 21;9:70
references.pmid: 18644122
references.citation: Am J Hum Genet. 2008 Mar;82(3):723-36
references.pmid: 18313025
references.citation: Gastroenterology. 2002 Oct;123(4):1109-19
references.pmid: 12360473
references.citation: BMC Cancer. 2009 Oct 20;9:374
references.pmid: 19843336
references.citation: Cancer Res. 2004 Dec 1;64(23):8558-65
references.pmid: 15574762
references.citation: Clin Genet. 2009 Mar;75(3):220-4
references.pmid: 19263514
references.citation: N Engl J Med. 2009 Oct 8;361(15):1475-85
references.pmid: 19812404
references.citation: Endocr Relat Cancer. 2006 Sep;13(3):839-49
references.pmid: 16954433
references.citation: Oncol Rep. 2007 Oct;18(4):943-51
references.pmid: 17786358
references.citation: Cancer Immunol Immunother. 2009 Feb;58(2):281-90
references.pmid: 18592235
references.citation: Nature. 2009 Apr 9;458(7239):719-24
references.pmid: 19360079
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Cancer Inform. 2007 Oct 12;3:341-55
references.pmid: 19455253
references.citation: Gut. 2009 Jan;58(1):79-89
references.pmid: 18829976
references.citation: N Engl J Med. 2008 Aug 14;359(7):722-34
references.pmid: 18703475
references.citation: Biostatistics. 2004 Oct;5(4):557-72
references.pmid: 15475419
references.citation: BMC Cancer. 2009 Jan 14;9:17
references.pmid: 19144156
references.citation: Cancer Res. 2006 Feb 15;66(4):2129-37
references.pmid: 16489013
references.citation: Cancer Res. 2008 Aug 1;68(15):6416-24
references.pmid: 18676867
references.citation: Nat Cell Biol. 2008 Feb;10(2):202-10
references.pmid: 18193036
references.citation: Oncol Rep. 2006 Mar;15(3):667-71
references.pmid: 16465428
references.citation: Blood. 2009 Mar 12;113(11):2478-87
references.pmid: 19147787
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16899-903
references.pmid: 12477932
references.citation: Nature. 2008 Nov 6;456(7218):66-72
references.pmid: 18987736
references.citation: Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1733-45
references.pmid: 17009964
references.citation: N Engl J Med. 2009 Dec 17;361(25):2449-60
references.pmid: 20018966
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: Cancer Cell. 2006 Apr;9(4):313-25
references.pmid: 16616336