KEGG   DISEASE: Hepatocellular carcinoma
Entry
H00048                      Disease                                

Name
Hepatocellular carcinoma;
Liver cancer
Description
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.
Category
Cancer
Brite
Human diseases [BR:br08402]
 Cancers
  Cancers of the digestive system
   H00048  Hepatocellular carcinoma
Human diseases in ICD-11 classification [BR:br08403]
 02 Neoplasms
  Malignant neoplasms, except of lymphoid, haematopoietic, central nervous system or related tissues
   Malignant neoplasms, stated or presumed to be primary, of specified sites, except of lymphoid, haematopoietic, central nervous system or related tissues
    Malignant neoplasms of digestive organs
     2C12  Malignant neoplasms of liver or intrahepatic bile ducts
      H00048  Hepatocellular carcinoma
Tumor markers [br08442.html]
 H00048
Cancer-associated carbohydrates [br08441.html]
 H00048
Pathway
hsa05225  Hepatocellular carcinoma
Network
nt06110  MAPK signaling (viruses and bacteria)
nt06114  PI3K signaling (viruses)
nt06118  TGFB signaling (viruses)
nt06119  JAK-STAT signaling (viruses)
nt06121  TLR signaling (viruses and bacteria)
nt06122  IFN signaling (viruses)
nt06123  TNF signaling (viruses and bacteria)
nt06124  Chemokine signaling (viruses)
nt06130  Cell cycle (viruses)
nt06131  Apoptosis (viruses and bacteria)
nt06133  RLR signaling (viruses)
nt06137  OAS/RNase L pathway (viruses)
nt06140  Transcription (viruses)
nt06162  Hepatitis B virus (HBV)
nt06163  Hepatitis C virus (HCV)
nt06263  Hepatocellular carcinoma
  Element
N00005  Mutation-activated MET to RAS-ERK signaling pathway
N00044  Mutation-activated MET to PI3K signaling pathway
N00049  Mutation-activated PI3K to PI3K signaling pathway
N00052  Mutation-inactivated PTEN to PI3K signaling pathway
N00058  Mutation-activated CTNNB1 to Wnt signaling pathway
N00059  FZD7-overexpression to Wnt signaling pathway
N00071  Deleted p16(INK4a) to p16-cell cycle G1/S
N00074  Loss of RB1 to cell cycle G1/S
N00115  Mutation-inactivated TP53 to transcription
N00228  TGFA-overexpression to PLCG-PKC signaling pathway
N00230  TGFA-overexpression to RAS-ERK signaling pathway
N00232  TGFA-overexpression to PI3K signaling pathway
N00235  IGF2-overexpression to RAS-ERK signaling pathway
N00236  IGF2-overexpression to PI3K signaling pathway
N00237  IGF1R-overexpression to RAS-ERK signaling pathway
N00238  IGF1R-overexpression to PI3K signaling pathway
N00240  TERT-overexpression to telomerase activity
N00241  TGFBR2-reduced expression to TGF-beta signaling pathway
N00242  Mutation-inactivated AXIN to Wnt signaling pathway
N00244  Mutation-inactivated KEAP1 to KEAP1-NRF2 signaling pathway
N00245  Mutation-activated NRF2 to KEAP1-NRF2 signaling pathway
N00246  HGF-overexpression to RAS-ERK signaling pathway
N00247  HGF-overexpression to PI3K signaling pathway
N00248  MET-overexpression to RAS-ERK signaling pathway
N00249  MET-overexpression to PI3K signaling pathway
N00267  HBV HBx to PI3K signaling pathway
N00268  HBV HBx to RIG-I-like receptor signaling pathway
N00269  HCV core to TNF-NFKB signaling pathway
N00270  HCV Core to IFN signaling pathway
N00271  HCV NS3/4A to RIG-I-like receptor signaling pathway
N00272  HCV NS5A to PI3K signaling pathway
N00273  HCV NS5A to oligoadenylate synthetase (OAS)/RNase L pathway
N00274  HCV NS5A to RAS-ERK signaling pathway
N00516  HCV NS3/4A to TLR3-IRF3 signaling pathway
N00517  HCV NS3/4A to TLR3-IRF3 signaling pathway
N00518  HCV Core to ERK signaling pathway
N00519  HCV Core to ERK signaling pathway
N00520  HCV NS5A to p21-cell cycle G1/S
N00521  HCV Core to p21-cell cycle G1/S
N00522  HCV NS3 to p21-cell cycle G1/S
N00523  HCV Core to p21-cell cycle G1/S
N00524  HCV NS5A to extrinsic apoptotic pathway
N00525  HCV NS5A to TNF-NFKB signaling pathway
N00526  HCV NS3 to crosstalk between extrinsic and intrinsic apoptotic pathways
N00527  HCV Core to crosstalk between extrinsic and intrinsic apoptotic pathways
N00528  HCV core to extrinsic apoptotic pathway
N00529  HCV core to RXRA/PPARA-mediated transcription
N00530  HCV core to RXRA/LXRA-mediated transcription
N00531  HBV HBx to TGF-beta signaling pathway
N00532  HBV HBx to Egr-mediated transcription
N00533  HBV HBx to Crosstalk between extrinsic and intrinsic apoptotic pathways
N00534  HBV HBx to Crosstalk between extrinsic and intrinsic apoptotic pathways
N00535  HBV HBx to p53-mediated transcription
N00537  HBV HBx to cell cycle G1/S
N00539  HBV HBx to Ca2+-PYK2-RAS-ERK signaling pathway
N00540  HBV HBx to RAS-ERK signaling pathway
N00541  HBV HBx to RAS-ERK signaling pathway
N00543  HBV HBx to JNK signaling pathway
N00544  HBV HBx to CREB-mediated transcription
N00545  HBV HBx to ERK signaling pathway
N00547  HBV LHBs to PKC-ERK signaling pathway
N00548  HBV HBx to Jak-STAT signaling pathway
N00549  HBV HBeAg to TLR2/4-NFKB signaling pathway
N00550  HBV HBeAg to TLR2/4-NFKB signaling pathway
N00551  HBV HBs to TLR2/4-MAPK signaling pathway
N00552  HBV pol to TLR3-IRF3 signaling pathway
N00554  HBV HBe to TLR4-IRF3/7 signaling pathway
N00555  HBV HBe to TLR4-IRF3/7 signaling pathway
N00556  HBV HBe to TLR2/4-NFKB signaling pathway
N00557  HBV HBe to TLR2/4-NFKB signaling pathway
N00558  HBV pol to IFN signaling pathway
Gene
TGFA (overexpression) [HSA:7039] [KO:K08774]
IGF2 (overexpression) [HSA:3481] [KO:K13769]
IGF1R (overexpression) [HSA:3480] [KO:K05087]
MYC (amplification) [HSA:4609] [KO:K04377]
RB1 (loss) [HSA:5925] [KO:K06618]
TERT (overexpression) [HSA:7015] [KO:K11126]
TP53 (mutation) [HSA:7157] [KO:K04451]
p16 (deletion) [HSA:1029] [KO:K06621]
PTEN (mutation) [HSA:5728] [KO:K01110]
TGFBR2 (reduced expression) [HSA:7048] [KO:K04388]
FZD7 (overexpression) [HSA:8324] [KO:K02432]
CTNNB1 (mutation) [HSA:1499] [KO:K02105]
AXIN1 (mutation) [HSA:8312] [KO:K02157]
KEAP1 (mutation) [HSA:9817] [KO:K10456]
NFE2L2 (mutation) [HSA:4780] [KO:K05638]
HGF (overexpression) [HSA:3082] [KO:K05460]
MET (mutation, overexpression) [HSA:4233] [KO:K05099]
PIK3CA (mutation) [HSA:5290] [KO:K00922]
ARID1A (mutation) [HSA:8289] [KO:K11653]
ARID2 (mutation) [HSA:196528] [KO:K11765]
Carcinogen
Aflatoxins (naturally occurring mixtures of) [CPD:C06800]
Alcoholic beverages
Opisthorchis viverrini (infection with)
Radium-224 and its decay products [CPD:C16455]
*Chimney sweeping
*2,3,7,8-Tetrachlorodibenzo-para-dioxin [CPD:C07557]
*Thorium-232 and its decay products, administered intravenously as a colloidal dispersion of thorium232 dioxide
*Tobacco smoking and tobacco smoke
*: Although this is a risk factor for liver cancer in general, the strength of association with different histological tumor types is not well understood.
Pathogen
Hepatitis B virus [GN:T40004]
Hepatitis C virus [GN:T40066]
Drug
Sorafenib tosylate [DR:D06272]
Regorafenib hydrate [DR:D10137]
Cabozantinib s-malate [DR:D10095]
Lenvatinib mesylate [DR:D09920]
Ipilimumab [DR:D04603]
Nivolumab [DR:D10316]
Pembrolizumab [DR:D10574]
Ramucirumab [DR:D09371]
Atezolizumab [DR:D10773]
Comment
ICD-O: 8170/3, Tumor type: Hepatocellular carcinoma (liver cell carcinoma)
Other DBs
ICD-11: 2C12.0
ICD-10: C22
MeSH: D006528
Reference
  Authors
Kudo M
  Title
Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma.
  Journal
Dig Dis 29:289-302 (2011)
DOI:10.1159/000327562
Reference
  Authors
Niu ZS, Niu XJ, Wang WH
  Title
Genetic alterations in hepatocellular carcinoma: An update.
  Journal
World J Gastroenterol 22:9069-9095 (2016)
DOI:10.3748/wjg.v22.i41.9069
Reference
  Authors
Breuhahn K, Longerich T, Schirmacher P
  Title
Dysregulation of growth factor signaling in human hepatocellular carcinoma.
  Journal
Oncogene 25:3787-800 (2006)
DOI:10.1038/sj.onc.1209556
Reference
  Authors
Whittaker S, Marais R, Zhu AX
  Title
The role of signaling pathways in the development and treatment of hepatocellular carcinoma.
  Journal
Oncogene 29:4989-5005 (2010)
DOI:10.1038/onc.2010.236
Reference
  Authors
Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM
  Title
Pathogenesis of hepatocellular carcinoma and molecular therapies.
  Journal
Curr Opin Gastroenterol 25:186-94 (2009)
DOI:10.1097/MOG.0b013e32832962a1
Reference
  Authors
Suriawinata A, Xu R
  Title
An update on the molecular genetics of hepatocellular carcinoma.
  Journal
Semin Liver Dis 24:77-88 (2004)
DOI:10.1055/s-2004-823102
Reference
  Authors
Taguchi K, Motohashi H, Yamamoto M
  Title
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.
  Journal
Genes Cells 16:123-40 (2011)
DOI:10.1111/j.1365-2443.2010.01473.x
Reference
  Authors
Yoo NJ, Kim HR, Kim YR, An CH, Lee SH
  Title
Somatic mutations of the KEAP1 gene in common solid cancers.
  Journal
Histopathology 60:943-52 (2012)
DOI:10.1111/j.1365-2559.2012.04178.x
Reference
  Authors
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clement B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouze 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 44:694-8 (2012)
DOI:10.1038/ng.2256
Reference
  Authors
Granito A, Guidetti E, Gramantieri L
  Title
c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.
  Journal
J Hepatocell Carcinoma 2:29-38 (2015)
DOI:10.2147/JHC.S77038
Reference
  Authors
Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH
  Title
PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.
  Journal
Oncogene 24:1477-80 (2005)
DOI:10.1038/sj.onc.1208304
Reference
  Authors
Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, Zhu ZD, Zhou B, Liu XY, Liu RF, Fei QL, Chen H, Cai B, Zhou B, Xiao HS, Qin LX, Han ZG
  Title
Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma.
  Journal
Nat Genet 44:1117-21 (2012)
DOI:10.1038/ng.2391
Reference
  Authors
Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J
  Title
High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
  Journal
Nat Commun 4:2218 (2013)
DOI:10.1038/ncomms3218
Reference
PMID:17295177 (gene, tumor type)
  Authors
Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM.
  Title
Genomics and signaling pathways in hepatocellular carcinoma.
  Journal
Semin Liver Dis 27:55-76 (2007)
DOI:10.1055/s-2006-960171
Reference
PMID:11935086 (gene, tumor type)
  Authors
Rocken C, Carl-McGrath S.
  Title
Pathology and pathogenesis of hepatocellular carcinoma.
  Journal
Dig Dis 19:269-78 (2001)
DOI:10.1159/000050693
Reference
PMID:17051452 (tumor type)
  Authors
Spangenberg HC, Thimme R, Blum HE.
  Title
Serum markers of hepatocellular carcinoma.
  Journal
Semin Liver Dis 26:385-90 (2006)
DOI:10.1055/s-2006-951606
Reference
  Authors
Thorgeirsson SS, Grisham JW.
  Title
Molecular pathogenesis of human hepatocellular carcinoma.
  Journal
Nat Genet 31:339-46 (2002)
DOI:10.1038/ng0802-339
Reference
PMID:15760280 (carcinogen)
  Authors
Schottenfeld D, Beebe-Dimmer JL.
  Title
Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions.
  Journal
Annu Rev Public Health 26:37-60 (2005)
DOI:10.1146/annurev.publhealth.26.021304.144402
Reference
PMID:15757802 (carcinogen)
  Authors
McGlynn KA, London WT.
  Title
Epidemiology and natural history of hepatocellular carcinoma.
  Journal
Best Pract Res Clin Gastroenterol 19:3-23 (2005)
DOI:10.1016/j.bpg.2004.10.004
Reference
PMID:15489140 (carcinogen)
  Authors
Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA.
  Title
Environmental and chemical carcinogenesis.
  Journal
Semin Cancer Biol 14:473-86 (2004)
DOI:10.1016/j.semcancer.2004.06.010
Reference
PMID:11285186 (carcinogen)
  Authors
Smela ME, Currier SS, Bailey EA, Essigmann JM.
  Title
The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis.
  Journal
Carcinogenesis 22:535-45 (2001)
DOI:10.1093/carcin/22.4.535
Reference
PMID:15928434 (carcinogen)
  Authors
Khurana S, Dubey ML, Malla N.
  Title
Association of parasitic infections and cancers.
  Journal
Indian J Med Microbiol 23:74-9 (2005)
DOI:10.4103/0255-0857.16044
Reference
PMID:10564925 (carcinogen)
  Authors
Nekolla EA, Kellerer AM, Kuse-Isingschulte M, Eder E, Spiess H.
  Title
Malignancies in patients treated with high doses of radium-224.
  Journal
Radiat Res 152:S3-7 (1999)
DOI:10.2307/3580102
Reference
PMID:9498904 (carcinogen)
  Authors
Boffetta P, Jourenkova N, Gustavsson P.
  Title
Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons.
  Journal
Cancer Causes Control 8:444-72 (1997)
DOI:10.1023/a:1018465507029
Reference
PMID:15660110 (carcinogen)
  Authors
Luch A.
  Title
Nature and nurture - lessons from chemical carcinogenesis.
  Journal
Nat Rev Cancer 5:113-25 (2005)
DOI:10.1038/nrc1546
Reference
PMID:12556326 (carcinogen)
  Authors
Harrison JD, Muirhead CR.
  Title
Quantitative comparisons of cancer induction in humans by internally deposited radionuclides and external radiation.
  Journal
Int J Radiat Biol 79:1-13 (2003)
DOI:10.1080/0955300021000038671

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