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

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
nt06505  WNT signaling
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]

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]
Tremelimumab [DR:D06657]

Other DBs

ICD-11:

2C12.0

ICD-10:

C22

MeSH:

D006528

OMIM:

114550

Reference

PMID:21829020

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

PMID:27895396

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

PMID:16799620

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

PMID:20639898

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

PMID:19387255

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

PMID:15085488

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

PMID:22922871

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

PMID:17295177

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

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:12149612

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

DISEASE: Hepatocellular carcinoma