Cancer gene discovery in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a deadly cancer, whose incidence is increasing worldwide. Albeit the main risk factors for HCC development have been clearly identified, such as hepatitis B and C virus infection and alcohol abuse, there is still preliminary understanding of the key drivers of this malignancy. Recent data suggest that genomic analysis of cirrhotic tissue - the pre-neoplastic carcinogenic field - may provide a read-out to identify at risk populations for cancer development. Given this contextual complexity, it is of utmost importance to characterize the molecular pathogenesis of this disease, and pinpoint the dominant pathways/drivers by integrative oncogenomic approaches and/or sophisticated experimental models. Identification of the dominant proliferative signals and key aberrations will allow for a more personalized therapy. Pathway-based approaches and functional experimental studies have aided in identifying the activation of different signaling cascades in HCC (e.g. epidermal growth factor, insulin-like growth factor, RAS, MTOR, WNT-betacatenin, etc.). However, the introduction of new high-throughput genomic technologies (e.g. microarrays, deep sequencing, etc.), and increased sophistication of computational biology (e.g. bioinformatics, biomodeling, etc.), opens the field to new strategies in oncogene and tumor suppressor discovery. These oncogenomic approaches are framed within emerging new disciplines such as systems biology, which integrates multiple inputs to explain cancer onset and progression. In addition, the consolidation of sophisticated animal models, such as mosaic cancer mouse models or the use of transposons for mutagenesis screens, have been instrumental for the identification of novel tumor drivers. We herein review some classical as well as some recent fast track approaches for oncogene discovery in HCC, and provide a comprehensive landscape of the currently known spectrum of molecular aberrations involved in hepatocarcinogenesis.
Zender
Lars
L
Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
Villanueva
Augusto
A
Tovar
Victoria
V
Sia
Daniela
D
Chiang
Derek Y
DY
Llovet
Josep M
JM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000235:genetics*
N Engl J Med. 2008 Jul 24;359(4):378-90
18650514
Oncogene. 2002 Mar 14;21(12):1791-9
11896611
Nature. 2004 Oct 28;431(7012):1112-7
15475948
N Engl J Med. 2009 Oct 8;361(15):1437-47
19812400
Nature. 2007 Mar 8;446(7132):153-8
17344846
Blood. 1998 Nov 15;92(10):3780-92
9808572
Gastroenterology. 2009 Jan;136(1):138-48
18848939
FEBS J. 2006 Mar;273(6):1102-14
16519677
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4171-7
16857788
Oncogene. 1995 Feb 16;10(4):765-8
7862454
Cancer Res. 2004 Jan 1;64(1):48-54
14729607
Gastroenterology. 2006 Apr;130(4):1117-28
16618406
Nature. 2004 Nov 18;432(7015):307-15
15549092
Nat Rev Cancer. 2008 Dec;8(12):915-28
19029956
FASEB J. 2001 Jun;15(8):1404-6
11387238
Hepatology. 2007 Jan;45(1):42-52
17187432
Hepatology. 2003 May;37(5):1105-13
12717391
Gastroenterology. 2008 Dec;135(6):1972-83, 1983.e1-11
18929564
Oncogene. 1989 Jun;4(6):715-24
2543942
J Hepatol. 2009 Oct;51(4):725-33
19665249
Cancer Lett. 2002 Feb 25;176(2):149-58
11804742
Cancer Res. 2008 Aug 15;68(16):6779-88
18701503
Nat Rev Cancer. 2006 Sep;6(9):674-87
16929323
J Clin Oncol. 2005 Sep 20;23(27):6657-63
16170173
Nature. 2009 Oct 1;461(7264):614-20
19759537
Oncogene. 2009 Feb 19;28(7):961-72
19137011
Genes Dev. 2008 Jun 1;22(11):1439-44
18519636
Nat Biotechnol. 2009 Mar;27(3):264-74
19234449
Science. 2002 Dec 6;298(5600):1911-2
12471242
Nat Rev Genet. 2008 May;9(5):329-40
18398419
Carcinogenesis. 2006 Apr;27(4):748-57
16339184
Hepatology. 2007 Aug;46(2):590-7
17661407
Hepatology. 1997 Apr;25(4):862-6
9096589
Cancer. 2005 Jan 15;103(2):307-12
15593087
Hepatology. 2007 May;45(5):1298-305
17464972
Oncogene. 2006 Jun 26;25(27):3787-800
16799620
J Clin Invest. 2006 Jun;116(6):1582-95
16710476
Mol Cancer Ther. 2007 Jan;6(1):1-12
17237261
JAMA. 2008 Jan 2;299(1):53-60
18167406
Nat Rev Genet. 2007 Jun;8(6):462-72
17510666
J Hepatol. 2008 May;48(5):858-79
18314222
Cancer. 2009 Oct 1;115(19):4576-85
19551889
Curr Opin Cell Biol. 2005 Dec;17(6):596-603
16226444
Nat Rev Drug Discov. 2006 Sep;5(9):741-54
16915232
Hum Mutat. 2003 Mar;21(3):201-16
12619106
Nat Genet. 1995 Dec;11(4):447-9
7493029
Cancer Cell. 2002 Apr;1(3):289-98
12086865
Cold Spring Harb Symp Quant Biol. 2005;70:251-61
16869761
Cancer Res. 1993 Apr 15;53(8):1719-23
8467484
J Med Invest. 2004 Aug;51(3-4):202-9
15460907
J Exp Clin Cancer Res. 1998 Mar;17(1):13-7
9646228
J Clin Invest. 2009 Mar;119(3):465-77
19221438
Nat Genet. 2003 Mar;33(3):396-400
12567186
Hepatology. 2002 Apr;35(4):834-42
11915029
Hepatology. 2005 Feb;41(2):307-14
15660382
Clin Cancer Res. 2008 Jun 15;14(12):3768-76
18559595
J Hepatol. 2010 Apr;52(4):550-9
20206398
Cancer. 2007 Sep 1;110(5):1059-67
17623837
Cancer Cell. 2009 Oct 6;16(4):295-308
19800575
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17059-64
16286660
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14771-6
17785413
Cold Spring Harb Symp Quant Biol. 2005;70:217-24
16869757
Cancer Res. 2004 Feb 15;64(4):1315-22
14973059
Nature. 2005 Aug 11;436(7052):807-11
16094360
N Engl J Med. 2008 Nov 6;359(19):1995-2004
18923165
Cancer Res. 2001 Jul 15;61(14):5389-95
11454681
Semin Liver Dis. 2007 Feb;27(1):55-76
17295177
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):143-8
12518062
Expert Rev Anticancer Ther. 2009 Feb;9(2):247-61
19192962
Nat Rev Cancer. 2006 Sep;6(9):729-34
16915295
Cell. 2002 Jan 25;108(2):135-44
11832204
Cancer Res. 2007 Mar 1;67(5):2081-8
17332337
Curr Opin Genet Dev. 2009 Feb;19(1):4-11
19201597
J Cell Biol. 2001 May 28;153(5):1023-34
11381087
Cell. 2009 Jun 12;137(6):1005-17
19524505
Int J Oncol. 2007 Aug;31(2):451-60
17611703
Cancer Cell. 2009 Oct 6;16(4):272-3
19800570
Science. 1994 May 27;264(5163):1317-9
8191284
Nature. 2008 Apr 3;452(7187):553-63
18385729
J Clin Invest. 2004 Jun;113(12):1774-83
15199412
Hepatology. 2008 Jun;47(6):2059-67
18506891
Differentiation. 2007 Nov;75(9):843-52
17999742
J Natl Cancer Inst. 2008 May 21;100(10):698-711
18477802
Cancer Cell. 2009 Feb 3;15(2):148-59
19185849
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17216-21
15563600
Cell. 2002 May 3;109(3):335-46
12015983
Cancer Res. 1996 Aug 15;56(16):3831-6
8706031
Nat Rev Drug Discov. 2008 Jun;7(6):504-16
18511928
Curr Biol. 2007 Dec 4;17(23):2054-60
17980593
Cell. 2006 Jun 30;125(7):1253-67
16814713
Cell. 1990 Jun 15;61(6):1137-46
2350785
Carcinogenesis. 2008 Jun;29(6):1087-91
18495658
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):701-6
9012848
Cell Growth Differ. 1996 Nov;7(11):1513-23
8930401
Br J Surg. 2004 Oct;91(10):1354-60
15376182
Lancet. 2003 Dec 6;362(9399):1907-17
14667750
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3389-94
15728360
Oncogene. 2000 Oct 19;19(44):5054-62
11042693
Science. 2007 Jul 6;317(5834):121-4
17615358
Science. 2007 Nov 16;318(5853):1108-13
17932254
Cell. 2008 Nov 28;135(5):852-64
19012953
Science. 2008 Dec 5;322(5907):1490-4
19056973
Cancer Cell. 2008 Feb;13(2):153-66
18242515