Genomic characterization of liver metastases from colorectal cancer patients.
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain.
José María
JM
Sayagués
Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain.
Luís Antonio
LA
Corchete
Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain.
María Laura
ML
Gutiérrez
Cáncer Research Center and Service of Hematology, University Hospital of Salamanca, Salamanca, Spain.
Maria Eugenia
ME
Sarasquete
Department of Pathology, University Hospital of Salamanca, Salamanca, Spain.
María
M
Del Mar Abad
Department of Pathology, University Hospital of Salamanca, Salamanca, Spain.
Oscar
O
Bengoechea
Genomics Unit, Cancer Research Center, IBMCC-CSIC/USAL, Salamanca, Spain.
Encarna
E
Fermiñán
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
María Fernanda
MF
Anduaga
Department of Pathology, University Hospital of Salamanca, Salamanca, Spain.
Sofia
S
Del Carmen
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Manuel
M
Iglesias
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Carmen
C
Esteban
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
María
M
Angoso
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Jose Antonio
JA
Alcazar
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Jacinto
J
García
Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center, IBMCC-CSIC/USAL and IBSAL, University of Salamanca, Salamanca, Spain.
Alberto
A
Orfao
Service of General and Gastrointestinal Surgery and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Luís
L
Muñoz-Bellvis
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D059467:Transcriptome
D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger
GEP; colorectal cancer
Science. 1987 Oct 9;238(4824):193-7
2889267
Clin Cancer Res. 2011 Apr 15;17(8):2444-50
21270110
Oncologist. 2015 Feb;20(2):127-33
25561511
Mol Biosyst. 2012 Nov;8(11):3077-88
22996014
Oncotarget. 2015 Aug 7;6(22):19070-86
26053098
J Natl Compr Canc Netw. 2011 Jan;9(1):13-25
21233242
Asian Pac J Cancer Prev. 2013;14(4):2201-5
23725112
Int J Clin Exp Pathol. 2015 Oct 01;8(10 ):12853-60
26722476
Biochem Biophys Res Commun. 2012 Oct 12;427(1):60-6
22982673
J Surg Oncol. 2015 Jun;111(7):905-10
25920435
J Clin Invest. 1995 Jan;95(1):55-65
7814646
Nucleic Acids Res. 2009 Jan;37(Database issue):D105-10
18996891
Compr Ther. 1989 May;15(5):14-22
2659250
Lancet Oncol. 2007 Jul;8(7):572-3
17613421
Nat Biotechnol. 2010 Dec;28(12):1248-50
21139605
Nature. 2007 Oct 11;449(7163):682-8
17898713
J Appl Genet. 2015 May;56(2):185-92
25366420
J Carcinog. 2009;8:10
19491504
Neoplasma. 2015 ;62(5):756-64
26278145
BMC Genomics. 2013 Aug 29;14:589
23987127
Int J Clin Exp Pathol. 2014 Feb 15;7(3):969-77
24696714
Nucleic Acids Res. 2014 Jan;42(Database issue):D959-65
24304897
Cancer Res. 2003 Apr 1;63(7):1568-75
12670906
Nucleic Acids Res. 2014 Jun;42(11):7170-85
24813441
Trends Pharmacol Sci. 2012 Jul;33(7):382-93
22613783
Biotechniques. 2003 Feb;34(2):374-8
12613259
Mod Pathol. 2012 Apr;25(4):590-601
22222638
Acta Biochim Biophys Sin (Shanghai). 2011 Mar;43(3):217-25
21242194
Biomark Res. 2013 Sep 18;1(1):27
24252756
PLoS One. 2011 Feb 24;6(2):e16636
21383983
PLoS One. 2011;6(8):e22566
21857934
Oncol Lett. 2015 Feb;9(2):869-874
25621061
BMC Bioinformatics. 2010 Apr 29;11:221
20429936
BMC Cancer. 2014 Feb 20;14:109
24555885
Tumour Biol. 2015 Sep;36(10 ):7641-7
25926384
Cancer Res. 2015 Aug 1;75(15):3010-9
26069251
Anticancer Res. 2012 Jun;32(6):2309-14
22641667
J Biol Chem. 2010 Mar 12;285(11):7986-94
20075075
PLoS One. 2013 Apr 12;8(4):e60861
23593331
J Natl Cancer Inst. 2015 Feb 06;107(3):null
25663689
BMC Cancer. 2008 Jul 01;8:187
18590575
Mol Oncol. 2014 Dec;8(8):1653-66
25049118
Cancer Sci. 2013 May;104(5):624-30
23373973
Cancer Biol Ther. 2015;16(7):1099-109
25955104
N Engl J Med. 1988 Sep 1;319(9):525-32
2841597
Br J Cancer. 2014 Aug 12;111(4):726-35
25025962
Oncotarget. 2014 Oct 15;5(19):9460-71
25294806
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
Stat Med. 1990 May;9(5):469-85
2349401
J Gastrointest Surg. 2007 May;11(5):660-5
17468927
Surgery. 2011 Nov;150(5):916-22
22018284
Carcinogenesis. 2007 Jun;28(6):1241-6
17259658
Br J Cancer. 2010 Jan 5;102(1):162-4
19953097
BMC Cancer. 2015 Dec 29;15:1023
26714817
Cancer Cell. 2015 Jun 8;27(6):809-21
25982816
Mol Med Rep. 2014 Jul;10(1):283-91
24737193
PLoS One. 2015 Jul 02;10(7):e0131699
26133168
Oncotarget. 2015 Nov 17;6(36):38695-704
26497852
J Biomed Inform. 2011 Oct;44(5):839-47
21605702