Hepatocellular carcinoma;
Liver cancer

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.

Cancer

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

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]

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.

Hepatitis B virus [GN:T40004]
Hepatitis C virus [GN:T40066]

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]

ICD-O: 8170/3, Tumor type: Hepatocellular carcinoma (liver cell carcinoma)

PMID:21829020

Kudo M

Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma.

Dig Dis 29:289-302 (2011)
DOI:10.1159/000327562

PMID:27895396

Niu ZS, Niu XJ, Wang WH

Genetic alterations in hepatocellular carcinoma: An update.

World J Gastroenterol 22:9069-9095 (2016)
DOI:10.3748/wjg.v22.i41.9069

PMID:16799620

Breuhahn K, Longerich T, Schirmacher P

Dysregulation of growth factor signaling in human hepatocellular carcinoma.

Oncogene 25:3787-800 (2006)
DOI:10.1038/sj.onc.1209556

PMID:20639898

Whittaker S, Marais R, Zhu AX

The role of signaling pathways in the development and treatment of hepatocellular carcinoma.

Oncogene 29:4989-5005 (2010)
DOI:10.1038/onc.2010.236

PMID:19387255

Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM

Pathogenesis of hepatocellular carcinoma and molecular therapies.

Curr Opin Gastroenterol 25:186-94 (2009)
DOI:10.1097/MOG.0b013e32832962a1

PMID:15085488

Suriawinata A, Xu R

An update on the molecular genetics of hepatocellular carcinoma.

Semin Liver Dis 24:77-88 (2004)
DOI:10.1055/s-2004-823102

PMID:21251164

Taguchi K, Motohashi H, Yamamoto M

Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.

Genes Cells 16:123-40 (2011)
DOI:10.1111/j.1365-2443.2010.01473.x

PMID:22348534

Yoo NJ, Kim HR, Kim YR, An CH, Lee SH

Somatic mutations of the KEAP1 gene in common solid cancers.

Histopathology 60:943-52 (2012)
DOI:10.1111/j.1365-2559.2012.04178.x

PMID:22561517

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

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

Nat Genet 44:694-8 (2012)
DOI:10.1038/ng.2256

PMID:27508192

Granito A, Guidetti E, Gramantieri L

c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.

J Hepatocell Carcinoma 2:29-38 (2015)
DOI:10.2147/JHC.S77038

PMID:15608678

Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.

Oncogene 24:1477-80 (2005)
DOI:10.1038/sj.onc.1208304

PMID:22922871

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

Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma.

Nat Genet 44:1117-21 (2012)
DOI:10.1038/ng.2391

PMID:23887712

Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J

High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.

Nat Commun 4:2218 (2013)
DOI:10.1038/ncomms3218

PMID:17295177 (gene, tumor type)

Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM.

Genomics and signaling pathways in hepatocellular carcinoma.

Semin Liver Dis 27:55-76 (2007)
DOI:10.1055/s-2006-960171

PMID:11935086 (gene, tumor type)

Rocken C, Carl-McGrath S.

Pathology and pathogenesis of hepatocellular carcinoma.

Dig Dis 19:269-78 (2001)
DOI:10.1159/000050693

PMID:17051452 (tumor type)

Spangenberg HC, Thimme R, Blum HE.

Serum markers of hepatocellular carcinoma.

Semin Liver Dis 26:385-90 (2006)
DOI:10.1055/s-2006-951606

PMID:12149612

Thorgeirsson SS, Grisham JW.

Molecular pathogenesis of human hepatocellular carcinoma.

Nat Genet 31:339-46 (2002)
DOI:10.1038/ng0802-339

PMID:15760280 (carcinogen)

Schottenfeld D, Beebe-Dimmer JL.

Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions.

Annu Rev Public Health 26:37-60 (2005)
DOI:10.1146/annurev.publhealth.26.021304.144402

PMID:15757802 (carcinogen)

McGlynn KA, London WT.

Epidemiology and natural history of hepatocellular carcinoma.

Best Pract Res Clin Gastroenterol 19:3-23 (2005)
DOI:10.1016/j.bpg.2004.10.004

PMID:15489140 (carcinogen)

Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA.

Environmental and chemical carcinogenesis.

Semin Cancer Biol 14:473-86 (2004)
DOI:10.1016/j.semcancer.2004.06.010

PMID:11285186 (carcinogen)

Smela ME, Currier SS, Bailey EA, Essigmann JM.

The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis.

Carcinogenesis 22:535-45 (2001)
DOI:10.1093/carcin/22.4.535

PMID:15928434 (carcinogen)

Khurana S, Dubey ML, Malla N.

Association of parasitic infections and cancers.

Indian J Med Microbiol 23:74-9 (2005)
DOI:10.4103/0255-0857.16044

PMID:10564925 (carcinogen)

Nekolla EA, Kellerer AM, Kuse-Isingschulte M, Eder E, Spiess H.

Malignancies in patients treated with high doses of radium-224.

Radiat Res 152:S3-7 (1999)
DOI:10.2307/3580102

PMID:9498904 (carcinogen)

Boffetta P, Jourenkova N, Gustavsson P.

Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons.

Cancer Causes Control 8:444-72 (1997)
DOI:10.1023/a:1018465507029

PMID:15660110 (carcinogen)

Luch A.

Nature and nurture - lessons from chemical carcinogenesis.

Nat Rev Cancer 5:113-25 (2005)
DOI:10.1038/nrc1546

PMID:12556326 (carcinogen)

Harrison JD, Muirhead CR.

Quantitative comparisons of cancer induction in humans by internally deposited radionuclides and external radiation.

Int J Radiat Biol 79:1-13 (2003)
DOI:10.1080/0955300021000038671