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*Chronic exposure of liver insult due to [[HBV infection]],[[HCV infection]],[[aflatoxin]],[[Non-alcoholic fatty liver disease|nonalcoholic steatohepatitis (NASH)]] causes damage to the [[Hepatocyte|hepatocytes]] induces a viscious circle of destruction and regeneration of hepatocytes which finally causes the activation of [[Stellate cell|stellate cells]] and hepatocyte senescence which contributes in the development of [[Liver Cirrhosis|cirrhosis]].
*Chronic exposure of liver insult due to [[HBV infection]],[[HCV infection]],[[aflatoxin]],[[Non-alcoholic fatty liver disease|nonalcoholic steatohepatitis (NASH)]] causes damage to the [[Hepatocyte|hepatocytes]] induces a viscious circle of destruction and regeneration of hepatocytes which finally causes the activation of [[Stellate cell|stellate cells]] and hepatocyte senescence which contributes in the development of [[Liver Cirrhosis|cirrhosis]].
*As a result of the genomic unstability the initiation of HCC occurs, step wise multiplication of different genetic events that lead to tumor progression and metastases are:<ref name="pmid23530248">{{cite journal |vauthors=Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IeM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H |title=TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=15 |pages=6021–6 |year=2013 |pmid=23530248 |pmc=3625331 |doi=10.1073/pnas.1303607110 |url=}}</ref><ref name="pmid23887712">{{cite journal |vauthors=Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J, Zucman Rossi J |title=High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions |journal=Nat Commun |volume=4 |issue= |pages=2218 |year=2013 |pmid=23887712 |pmc=3731665 |doi=10.1038/ncomms3218 |url=}}</ref><ref name="pmid24866078">{{cite journal |vauthors=Chen YL, Jeng YM, Chang CN, Lee HJ, Hsu HC, Lai PL, Yuan RH |title=TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection |journal=Int J Surg |volume=12 |issue=7 |pages=659–65 |year=2014 |pmid=24866078 |doi=10.1016/j.ijsu.2014.05.066 |url=}}</ref><ref name="pmid25822088">{{cite journal |vauthors=Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J |title=Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets |journal=Nat. Genet. |volume=47 |issue=5 |pages=505–511 |year=2015 |pmid=25822088 |pmc=4587544 |doi=10.1038/ng.3252 |url=}}</ref><ref name="pmid25362482">{{cite journal |vauthors=Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, Ojima H, Shimada K, Midorikawa Y, Goss JA, Cotton R, Hayashi A, Shibahara J, Ishikawa S, Guiteau J, Tanaka M, Urushidate T, Ohashi S, Okada N, Doddapaneni H, Wang M, Zhu Y, Dinh H, Okusaka T, Kokudo N, Kosuge T, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T |title=Trans-ancestry mutational landscape of hepatocellular carcinoma genomes |journal=Nat. Genet. |volume=46 |issue=12 |pages=1267–73 |year=2014 |pmid=25362482 |doi=10.1038/ng.3126 |url=}}</ref><ref name="pmid23728943">{{cite journal |vauthors=Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, Tan TX, Wu MC, Getz G, Lawrence MS, Parker JS, Li J, Powers S, Kim H, Fischer S, Guindi M, Ghanekar A, Chiang DY |title=Identification of driver genes in hepatocellular carcinoma by exome sequencing |journal=Hepatology |volume=58 |issue=5 |pages=1693–702 |year=2013 |pmid=23728943 |pmc=3830584 |doi=10.1002/hep.26540 |url=}}</ref><ref name="pmid17401425">{{cite journal |vauthors=Hussain SP, Schwank J, Staib F, Wang XW, Harris CC |title=TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer |journal=Oncogene |volume=26 |issue=15 |pages=2166–76 |year=2007 |pmid=17401425 |doi=10.1038/sj.onc.1210279 |url=}}</ref><ref name="pmid22561517">{{cite journal |vauthors=Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J |title=Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma |journal=Nat. Genet. |volume=44 |issue=6 |pages=694–8 |year=2012 |pmid=22561517 |pmc=3819251 |doi=10.1038/ng.2256 |url=}}</ref><ref name="pmid23788652">{{cite journal |vauthors=Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M |title=Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma |journal=Genome Res. |volume=23 |issue=9 |pages=1422–33 |year=2013 |pmid=23788652 |pmc=3759719 |doi=10.1101/gr.154492.113 |url=}}</ref>
*As a result of the genomic unstability the initiation of HCC occurs, step wise multiplication of different genetic events that lead to tumor progression and metastases are:
**[[Gene]] rearrangements
**[[Gene]] rearrangements
**[[Somatic]] mutations
**[[Somatic]] mutations
Line 32: Line 32:
**[[Growth factor]] pathway alterations  
**[[Growth factor]] pathway alterations  
**[[Molecule|Molecular]] pathway alterations  
**[[Molecule|Molecular]] pathway alterations  
*The major molecular events that occur in the pathogenesis of hepatocellular carcinoma are:
*The major molecular events that occur in the pathogenesis of hepatocellular carcinoma are:<ref name="pmid23530248">{{cite journal |vauthors=Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IeM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H |title=TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=15 |pages=6021–6 |year=2013 |pmid=23530248 |pmc=3625331 |doi=10.1073/pnas.1303607110 |url=}}</ref><ref name="pmid23887712">{{cite journal |vauthors=Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J, Zucman Rossi J |title=High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions |journal=Nat Commun |volume=4 |issue= |pages=2218 |year=2013 |pmid=23887712 |pmc=3731665 |doi=10.1038/ncomms3218 |url=}}</ref><ref name="pmid24866078">{{cite journal |vauthors=Chen YL, Jeng YM, Chang CN, Lee HJ, Hsu HC, Lai PL, Yuan RH |title=TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection |journal=Int J Surg |volume=12 |issue=7 |pages=659–65 |year=2014 |pmid=24866078 |doi=10.1016/j.ijsu.2014.05.066 |url=}}</ref><ref name="pmid25822088">{{cite journal |vauthors=Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J |title=Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets |journal=Nat. Genet. |volume=47 |issue=5 |pages=505–511 |year=2015 |pmid=25822088 |pmc=4587544 |doi=10.1038/ng.3252 |url=}}</ref><ref name="pmid25362482">{{cite journal |vauthors=Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, Ojima H, Shimada K, Midorikawa Y, Goss JA, Cotton R, Hayashi A, Shibahara J, Ishikawa S, Guiteau J, Tanaka M, Urushidate T, Ohashi S, Okada N, Doddapaneni H, Wang M, Zhu Y, Dinh H, Okusaka T, Kokudo N, Kosuge T, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T |title=Trans-ancestry mutational landscape of hepatocellular carcinoma genomes |journal=Nat. Genet. |volume=46 |issue=12 |pages=1267–73 |year=2014 |pmid=25362482 |doi=10.1038/ng.3126 |url=}}</ref><ref name="pmid23728943">{{cite journal |vauthors=Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, Tan TX, Wu MC, Getz G, Lawrence MS, Parker JS, Li J, Powers S, Kim H, Fischer S, Guindi M, Ghanekar A, Chiang DY |title=Identification of driver genes in hepatocellular carcinoma by exome sequencing |journal=Hepatology |volume=58 |issue=5 |pages=1693–702 |year=2013 |pmid=23728943 |pmc=3830584 |doi=10.1002/hep.26540 |url=}}</ref><ref name="pmid17401425">{{cite journal |vauthors=Hussain SP, Schwank J, Staib F, Wang XW, Harris CC |title=TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer |journal=Oncogene |volume=26 |issue=15 |pages=2166–76 |year=2007 |pmid=17401425 |doi=10.1038/sj.onc.1210279 |url=}}</ref><ref name="pmid22561517">{{cite journal |vauthors=Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J |title=Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma |journal=Nat. Genet. |volume=44 |issue=6 |pages=694–8 |year=2012 |pmid=22561517 |pmc=3819251 |doi=10.1038/ng.2256 |url=}}</ref><ref name="pmid23788652">{{cite journal |vauthors=Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M |title=Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma |journal=Genome Res. |volume=23 |issue=9 |pages=1422–33 |year=2013 |pmid=23788652 |pmc=3759719 |doi=10.1101/gr.154492.113 |url=}}</ref><ref name="pmid1682737">{{cite journal |vauthors=Ozturk M |title=p53 mutation in hepatocellular carcinoma after aflatoxin exposure |journal=Lancet |volume=338 |issue=8779 |pages=1356–9 |year=1991 |pmid=1682737 |doi= |url=}}</ref><ref name="pmid12388740">{{cite journal |vauthors=Madden CR, Finegold MJ, Slagle BL |title=Altered DNA mutation spectrum in aflatoxin b1-treated transgenic mice that express the hepatitis B virus x protein |journal=J. Virol. |volume=76 |issue=22 |pages=11770–4 |year=2002 |pmid=12388740 |pmc=136763 |doi= |url=}}</ref><ref name="pmid24395088">{{cite journal |vauthors=Villanueva A, Llovet JM |title=Liver cancer in 2013: Mutational landscape of HCC--the end of the beginning |journal=Nat Rev Clin Oncol |volume=11 |issue=2 |pages=73–4 |year=2014 |pmid=24395088 |doi=10.1038/nrclinonc.2013.243 |url=}}</ref><ref name="pmid23505090">{{cite journal |vauthors=Wang K, Lim HY, Shi S, Lee J, Deng S, Xie T, Zhu Z, Wang Y, Pocalyko D, Yang WJ, Rejto PA, Mao M, Park CK, Xu J |title=Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma |journal=Hepatology |volume=58 |issue=2 |pages=706–17 |year=2013 |pmid=23505090 |doi=10.1002/hep.26402 |url=}}</ref><ref name="pmid17534893">{{cite journal |vauthors=Su PF, Lee TC, Lin PJ, Lee PH, Jeng YM, Chen CH, Liang JD, Chiou LL, Huang GT, Lee HS |title=Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma |journal=Int. J. Cancer |volume=121 |issue=6 |pages=1257–64 |year=2007 |pmid=17534893 |doi=10.1002/ijc.22849 |url=}}</ref><ref name="pmid9892188">{{cite journal |vauthors=Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, Lai PB, Lau WY, Hjelm NM, Johnson PJ |title=Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients |journal=Cancer Res. |volume=59 |issue=1 |pages=71–3 |year=1999 |pmid=9892188 |doi= |url=}}</ref><ref name="pmid11948118">{{cite journal |vauthors=Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ |title=Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas |journal=Clin. Cancer Res. |volume=8 |issue=4 |pages=1087–92 |year=2002 |pmid=11948118 |doi= |url=}}</ref>
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{{familytree | | | | | | | | | | | | | | | | | | | | | | | A01 |A01='''Major molecular events in the pathogenesis of HCC'''}}  
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Revision as of 15:19, 18 January 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Overview

The exact pathogenesis of hepatocellular carcinoma HCC is not fully understood. It is thought that HCC is mediated by either HBV infection, HCV infection, underlying cirrhotic liver disease, inflammation, necrosis and fibrosis. On microscopic histopathological analysis, large polygonal tumours cells with graunular eosinophilic cytoplasm or layered dense collagen bundles are characteristic findings of hepatocellular carcinoma.

Pathophysiology

Pathogenesis

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Major molecular events in the pathogenesis of HCC
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epigenetic modifications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growthfactor pathway alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gene Mutations
 
Gene Amplification
 
 
 
 
 
 
 
DNA methylation micro RNA
 
 
 
 
Micro RNA
 
 
 
 
 
LNC RNA
 
 
 
 
 
 
Major Signaling pathways
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•TERT promoter
•TP53
•CTNNB1
•AXIN1
•AXIN2
•ATM
•RPS6KA3
•JAK1
•IL6R
•IL6ST
•ARID1
•ARID2
 
•CCND1
•FGF19
•CDKNA2A
•CDKNA2B
•AXIN1
•IRF2
•MET
 
 
 
 
 
 
 
GSTP1
•E-cadherin
•CDKNA2
•RASSF1A
•SOCS3
•MIGMT
 
 
 
 
•MiR-155
•MiR-122
•MiR-224
•MiR-21
 
 
 
 
 
•HULC
•HEIH
•Dreh
•MVIH
•HOTAIR
•MDIG
•LINE1
 
 
 
 
 
 
•Wnt/β–catenin
•Tyrosine kinase pathways
EGF
HGF/c-MET
FGF
VEGF
•IGF
•HIF1
•HIF2
•TGF β
•Hedgehog

To review the pathogenesis of HBV infection, click here.

To review the pathogenesis of HCV infection click here.

To review the pathogenesis of hepatic cirrhosis, click here.

Genetics

  • As of now there is no significant manifestation of an ordered cycle of genomic events leading to hepatocarcinogenesis. The pattern of genomic transformations exhibit huge variations often between two different HCCs from a single patient.
  • Hepatocellular carcinoma is most commonly implicated with underlying chronic hepatitis and liver cirrhosis, however differen genes have been associated with the pathogenesis of the HCC, which are further divided into four major groups:[2][19]
    • Genes regulating DNA damage response
    • Genes involved in cell cycle control
    • Genes involved in growth inhibition and apoptosis
    • Genes responsible for cell–cell interaction and signal transduction.
  • Genes involved in the pathogenesis of hepatocellular carcinoma include:

Associated Conditions

The associated conditions with hepatocellular carcinoma are

  • HBV infection
  • HCV infection
  • Underlying cirrhotic liver disease
  • Inflammation
  • Necrosis and fibrosis of the liver

Microscopic Pathology

  • On microscopic histopathological analysis, large polygonal tumours cells with graunular eosinophilic cytoplasm or layered dense collagen bundles are characteristic findings of hepatocellular carcinoma.

Gross Pathology

On gross pathology, hepatocellular carcinoma has the following characteristic findings:[20]

  • Nodular or diffusely infiltrative.
  • The nodular type may be unifocal (large mass) or multifocal (when developed as a complication of cirrhosis). Tumor nodules are round to oval, grey or green (if the tumor produces bile), well circumscribed but not encapsulated.
  • In about fifty percent of the cases, the tumors are multifocal where as some authors have suggested it to be around 75 percent.
  • The portal vein is infiltrated by the poorly circumcised diffused type and the hepatic veins are rarely infiltrated.
  • Pale in relation to surrounding liver or green (due to bile secretion)
  • Hepatocelluler carcinoma. The image shows a longitudinal slice taken through the full length of the liver. (Courtesy of Ed Uthman, MD)

    Hepatocelluler carcinoma. The image shows a longitudinal slice taken through the full length of the liver.
    (Courtesy of Ed Uthman, MD)

  • The tumor is at the top, cirrhotic liver at the bottom, and a fibrous reaction in between. Hepatocellular carcinomas can have a variety of gross patterns, including multinodular / multifocal, such as this one. (Courtesy of Ed Uthman, MD)

    The tumor is at the top, cirrhotic liver at the bottom, and a fibrous reaction in between. Hepatocellular carcinomas can have a variety of gross patterns, including multinodular / multifocal, such as this one.
    (Courtesy of Ed Uthman, MD)

Microscopic Pathology

On microscopic histopathological analysis, hepatocellular carcinoma has the following characteristic findings:

  • Large polygonal tumours cells with:
  • Graunular eosinophilic cytoplasm
  • Low NC ratio
  • Layered dense collagen bundles [21]

Videos

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References

  1. ↑ Röcken C, Carl-McGrath S (2001). "Pathology and pathogenesis of hepatocellular carcinoma". Dig Dis. 19 (4): 269–78. doi:10.1159/000050693. PMID 11935086.
  2. ↑ 2.0 2.1 Dhanasekaran R, Bandoh S, Roberts LR (2016). "Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances". F1000Res. 5. doi:10.12688/f1000research.6946.1. PMC 4870992. PMID 27239288.
  3. ↑ Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih I, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H (2013). "TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal". Proc. Natl. Acad. Sci. U.S.A. 110 (15): 6021–6. doi:10.1073/pnas.1303607110. PMC 3625331. PMID 23530248. Vancouver style error: initials (help)
  4. ↑ Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J, Zucman Rossi J (2013). "High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions". Nat Commun. 4: 2218. doi:10.1038/ncomms3218. PMC 3731665. PMID 23887712.
  5. ↑ Chen YL, Jeng YM, Chang CN, Lee HJ, Hsu HC, Lai PL, Yuan RH (2014). "TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection". Int J Surg. 12 (7): 659–65. doi:10.1016/j.ijsu.2014.05.066. PMID 24866078.
  6. ↑ Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J (2015). "Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets". Nat. Genet. 47 (5): 505–511. doi:10.1038/ng.3252. PMC 4587544. PMID 25822088.
  7. ↑ Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, Ojima H, Shimada K, Midorikawa Y, Goss JA, Cotton R, Hayashi A, Shibahara J, Ishikawa S, Guiteau J, Tanaka M, Urushidate T, Ohashi S, Okada N, Doddapaneni H, Wang M, Zhu Y, Dinh H, Okusaka T, Kokudo N, Kosuge T, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T (2014). "Trans-ancestry mutational landscape of hepatocellular carcinoma genomes". Nat. Genet. 46 (12): 1267–73. doi:10.1038/ng.3126. PMID 25362482.
  8. ↑ Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, Tan TX, Wu MC, Getz G, Lawrence MS, Parker JS, Li J, Powers S, Kim H, Fischer S, Guindi M, Ghanekar A, Chiang DY (2013). "Identification of driver genes in hepatocellular carcinoma by exome sequencing". Hepatology. 58 (5): 1693–702. doi:10.1002/hep.26540. PMC 3830584. PMID 23728943.
  9. ↑ Hussain SP, Schwank J, Staib F, Wang XW, Harris CC (2007). "TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer". Oncogene. 26 (15): 2166–76. doi:10.1038/sj.onc.1210279. PMID 17401425.
  10. ↑ Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J (2012). "Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma". Nat. Genet. 44 (6): 694–8. doi:10.1038/ng.2256. PMC 3819251. PMID 22561517.
  11. ↑ Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M (2013). "Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma". Genome Res. 23 (9): 1422–33. doi:10.1101/gr.154492.113. PMC 3759719. PMID 23788652.
  12. ↑ Ozturk M (1991). "p53 mutation in hepatocellular carcinoma after aflatoxin exposure". Lancet. 338 (8779): 1356–9. PMID 1682737.
  13. ↑ Madden CR, Finegold MJ, Slagle BL (2002). "Altered DNA mutation spectrum in aflatoxin b1-treated transgenic mice that express the hepatitis B virus x protein". J. Virol. 76 (22): 11770–4. PMC 136763. PMID 12388740.
  14. ↑ Villanueva A, Llovet JM (2014). "Liver cancer in 2013: Mutational landscape of HCC--the end of the beginning". Nat Rev Clin Oncol. 11 (2): 73–4. doi:10.1038/nrclinonc.2013.243. PMID 24395088.
  15. ↑ Wang K, Lim HY, Shi S, Lee J, Deng S, Xie T, Zhu Z, Wang Y, Pocalyko D, Yang WJ, Rejto PA, Mao M, Park CK, Xu J (2013). "Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma". Hepatology. 58 (2): 706–17. doi:10.1002/hep.26402. PMID 23505090.
  16. ↑ Su PF, Lee TC, Lin PJ, Lee PH, Jeng YM, Chen CH, Liang JD, Chiou LL, Huang GT, Lee HS (2007). "Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma". Int. J. Cancer. 121 (6): 1257–64. doi:10.1002/ijc.22849. PMID 17534893.
  17. ↑ Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, Lai PB, Lau WY, Hjelm NM, Johnson PJ (1999). "Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients". Cancer Res. 59 (1): 71–3. PMID 9892188.
  18. ↑ Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ (2002). "Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas". Clin. Cancer Res. 8 (4): 1087–92. PMID 11948118.
  19. ↑ Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW (2011). "Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma". Nat. Genet. 43 (9): 828–9. doi:10.1038/ng.903. PMC 3163746. PMID 21822264.
  20. ↑ Reynolds AR, Furlan A, Fetzer DT, Sasatomi E, Borhani AA, Heller MT, Tublin ME (2015). "Infiltrative hepatocellular carcinoma: what radiologists need to know". Radiographics. 35 (2): 371–86. doi:10.1148/rg.352140114. PMID 25763723.
  21. ↑ "Hepatocellular carcinoma".


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