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 primary neoplasms 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
Related
pathway
hsa05161  Hepatitis B
hsa05160  Hepatitis C
hsa05200  Pathways in cancer
hsa05206  MicroRNAs in cancer
Network
nt06110  MAPK signaling (viruses and bacteria)
nt06114  PI3K 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
nt06507  TGFB signaling
Gene
TGFA (overexpression) [HSA:7039] [KO:K08774]
IGF2 (overexpression) [HSA:3481] [KO:K13769]
IGF1R (overexpression) [HSA:3480] [KO:K05087]
TERT (overexpression) [HSA:7015] [KO:K11126]
FZD7 (overexpression) [HSA:8324] [KO:K02432]
HGF (overexpression) [HSA:3082] [KO:K05460]
MET (mutation, overexpression) [HSA:4233] [KO:K05099]
MYC (amplification) [HSA:4609] [KO:K04377]
RB1 (loss) [HSA:5925] [KO:K06618]
CDKN2A (deletion) [HSA:1029] [KO:K06621]
TGFBR2 (reduced expression) [HSA:7048] [KO:K04388]
TP53 [HSA:7157] [KO:K04451]
PTEN [HSA:5728] [KO:K01110]
CTNNB1 [HSA:1499] [KO:K02105]
AXIN1 [HSA:8312] [KO:K02157]
KEAP1 [HSA:9817] [KO:K10456]
NFE2L2 [HSA:4780] [KO:K05638]
PIK3CA [HSA:5290] [KO:K00922]
ARID1A [HSA:8289] [KO:K11653]
ARID2 [HSA:196528] [KO:K11765]
CASP8 [HSA:841] [KO:K04398]
IGF2R [HSA:3482] [KO:K06564]
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]
Nivolumab [DR:D10316]
Pembrolizumab [DR:D10574]
Atezolizumab [DR:D10773]
Bevacizumab [DR:D06409]
Ramucirumab [DR:D09371]
Ipilimumab [DR:D04603]
Other DBs
ICD-11: 2C12.0
ICD-10: C22
MeSH: D006528
OMIM: 114550
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
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
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
  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
  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:21251164 (KEAP1, NFE2L2)
  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
PMID:22348534 (KEAP1, NFE2L2)
  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
PMID:22561517 (CTNNB1, AXIN1, ARID1A, ARID2)
  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
PMID:27508192 (MET)
  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
PMID:15608678 (PIK3CA)
  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
PMID:23887712 (TERT)
  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:15531912 (CASP8)
  Authors
Soung YH, Lee JW, Kim SY, Sung YJ, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH
  Title
Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas.
  Journal
Oncogene 24:141-7 (2005)
DOI:10.1038/sj.onc.1208244
Reference
PMID:7493029 (IGF2R)
  Authors
De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL
  Title
M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity.
  Journal
Nat Genet 11:447-9 (1995)
DOI:10.1038/ng1295-447

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