Cholangiocarcinoma, Susceptibility To

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Retrieved

2019-09-22

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Omim

Trials

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Genes

TP53, IDH1, IDH2, RNF43, KRAS, PTGS2, IL6, EGFR, FGFR2, ERBB2, BRAF, PTEN, BAP1, PRKACB, SMAD4, MSLN, GNAS, SLC5A5, PTPN3, ARID1A, NOS2, PBRM1, PRKACA, PEG3, ROBO2, KMT2C, MET, TGFB1, HGF, MUC1

TP53, IDH1, IDH2, RNF43, KRAS, PTGS2, IL6, EGFR, FGFR2, ERBB2, BRAF, PTEN, BAP1, PRKACB, SMAD4, MSLN, GNAS, SLC5A5, PTPN3, ARID1A, NOS2, PBRM1, PRKACA, PEG3, ROBO2, KMT2C, MET, TGFB1, HGF, MUC1, MMP9, MMP2, NR1H4, SOX17, EPOR, TNC, MUC4, TGFBR2, EPO, DCTN4, AKT1, SP140, KRT19, GPR35, MCL1, CDKN2A, MST1, CD274, BCL2, SP110, TNF, IFNL3, TCF4, STAT3, CTNNB1, VEGFA, MIR21, CEACAM5, MAPK1, ROS1, PIK3CA, MTCO2P12, COX2, ALB, AFP, ASPH, CXCL12, CEACAM3, MIR122, FBXW7, NQO1, CEACAM7, KDR, EZH2, FBN2, EGF, DNMT1, CCND1, GPBAR1, TNFSF10, PPFIBP2, YAP1, CXCR4, PSG2, PROM1, PIK3CG, PIK3CD, PIK3CB, NOTCH1, MIR34A, EPHB2, GRAP2, POLDIP2, RNF19A, RASSF1, ESR1, AHSA1, MTHFR, HPGD, SLC7A5, NEK2, AIMP2, VDR, IFI27, TERT, IL10, MAP2K7, PPARG, SFRP1, H3P10, APC, CASP3, CRK, CDKN1B, MAPK14, CD44, DAPK1, MUC5AC, SPRR2A, FOXM1, KHDRBS1, DCTN6, NFE2L2, POU5F1P4, MIR200B, MUC2, AFAP1-AS1, POU5F1P3, NR1I2, SLC22A1, ZNRD2, GATA6, KLHL1, AICDA, CBR1, PDR, CDK2, ABCB1, PKM, PSMD9, POU5F1, TMED7, MAPK3, GABPA, UCA1, MIR192, RHOC, LCN2, ABCC2, XIAP, SOX2-OT, IL6R, TMED7-TICAM2, LOXL2, HDAC3, TICAM2, DCC, H3P23, ACE, SYCE1L, MAOA, IL33, MDM2, MUC16, EPCAM, TLR4, CD47, L1CAM, PHB, WWOX, C17orf97, KRT20, KIT, PPIA, PPARD, RPSA, NOTCH3, MEG3, TP73-AS1, LDHA, OGG1, SARNP, LGALS3, CDK4, NOS3, PDGFD, MYC, MUTYH, TACSTD2, CHRNA4, CDX2, ARHGAP24, ALOX5, PDCD4, PRKAR1A, STS, BAX, ANXA5, TFF1, DLC1, TGM2, APEX1, TP73, HDAC6, TPM1, HSP90B1, TYMS, VIM, MAP2K1, XRCC1, AQP1, CLOCK, FAS, NR0B2, SLC9A3R1, S1PR2, ABCB11, ABCC3, SOCS3, SQSTM1, PDPN, POSTN, ZEB1, SST, FOXP3, IL22, CD14, PYCARD, CCNB1, CCK, PTPN6, ITGB1, RAF1, BBC3, RARG, LAT, NUP62, SMUG1, CBX5, SCTR, BSG, SLC22A3, SNAI2, FSCN1, SOX2, SOX4, SPP1, MIR106B, NAT1, CRYZ, MIR200C, IL1B, HSP90AA1, FOXO3, GCG, HIF1A, HK2, IGF2, MIR204, HOXD9, FHIT, CRP, FBP1, HMOX1, MIR494, FOXO1, FOLH1, MIR186, MIR29A, FLT4, CD24, MIR149, FLT1, NNT-AS1, GSTP1, GLI1, GPC3, MIR221, IRF1, GRN, HES1, MIR210, CXCR2, PTK2B, GLP1R, MIR551B, GSTT1, LOC110806263, SFN, F2RL1, MIR370, GTF2H1, CTLA4, ZHX1, ANXA2, HRH3, METAP2, ANXA4, IGF2BP3, FLVCR1-DT, COPS5, KCNQ1OT1, PAPOLA, MALT1, MRPS30, HPSE, GGTLC5P, MIR10A, MORC2, PARK7, MIR483, GNMT, INTU, MIR361, ACAD8, ANGPT2, WWTR1, ANXA1, MIR378A, DCAF12, SHC2, SNHG1, MIR383, DUXAP9, BRD4, MIR429, SIRT3, ARL6IP1, MIR410, TBC1D9, ZNF423, SIRT2, MMRN1, KLRK1, TUSC2, MIR485, MIR490, PDAP1, RAD51AP1, KAT5, NME1-NME2, HTATIP2, SPRY4-IT1, ZFYVE9, COMMD3-BMI1, KLRC4-KLRK1, ABCG2, GSTO1, PTGES, CHD1L, CCAT1, PCAT6, CREB5, PRDX6, WTAP, ABCG1, LINC01503, CD163, TRIP10, PANDAR, MTA1, LNCRNA-ATB, SPHK1, MCM3AP, AADAC, PKD2L1, USP14, NEURL1, BLACAT1, EBAG9, TMSB10, CDR1-AS, DCLK1, PTTG1, COPB2, SETD1A, HDAC4, MIR1299, MIR92B, TSPAN1, LRPPRC, MAGED4, ABI2, GGTLC3, AKR1A1, MIR637, GGT2, MIR622, TACC3, SEMA4D, CIB1, MIR340, MIR612, PDCD6IP, HULC, MAGI2, WDR1, LMCD1-AS1, LOXL1-AS1, TLK1, NUAK1, KLHL21, DLEC1, SLC23A2, SRA1, FGF19, NR1I3, BIRC3, ZGLP1, NR2E3, GGTLC4P, BHLHE22, ASAP1, MIR330, NLRP3, MIR22HG, MIR191, DNER, MIR15A, BMS1P20, AZIN2, MIR155HG, PWAR1, LRG1, RBM45, CKS1BP7, ACTRT1, GATA5, LINC00261, MIR195, DPY30, MIR199A1, HSDL2, MINDY4, SESN2, MIR199A2, MAGED4B, MIR19A, MIR200A, SLC38A1, MIR203A, TET1, ACTB, ZNF703, WLS, EHMT1, PRIMA1, PDIK1L, NEIL1, C1QL3, MIR144, MIR141, MIR140, LINC-PINT, MALAT1, MIR132, FENDRR, APLNR, MIR129-2, TEX41, LINC01061, MIRLET7C, MIR126, MIR106A, MACC1, GADL1, MIR145, FFAR4, RAB7B, TRIM59, MIR146A, NEK8, NEAT1, H19, AP2A1, COMMD6, CBLL2, AGR3, MIR150, MIR152, DAB2IP, VTCN1, MUL1, MAGEH1, TLR7, LEF1, CLDN18, CDKL3, ACP3, GOLM1, MIR31, ZBTB7A, UGT1A10, ZMYND10, SIRT7, GDE1, SRRT, MPC1, MIR30E, MIR99A, EGFL7, MIR17HG, SDF4, ANGPTL4, TNNI3K, PI15, ZFAS1, PARP1, XRCC6P5, RRM2B, MIR151A, ERO1A, ALOX15, MIR324, SETD2, ASAP1-IT1, MIR30D, ALDOA, SLC52A2, ABCG8, SALL4, MIR23B, MIR222, ALCAM, AFAP1, ALX4, AHSG, TUG1, CRTC3, SPATA20, MARCKSL1, MIR22, ASAP2, PAGR1, AKR1B10, ACKR3, CA10, SPHK2, ERBIN, PBK, LAPTM4B, MIR25, ALDH1A1, MIR26B, CCDC25, ALDH1A3, MTPAP, MIR296, PIWIL2, AKIRIN2, SLC52A1, GGCT, GADD45A, APOA1, MAGEA3, KRT18, CKS1B, LAMC2, STMN1, LASP1, LCK, LDLR, LEP, LGALS1, LGALS9, LIF, LMNA, LPA, MARCKS, SMAD2, CISH, MAFG, KRT7, CKS2, KPNA2, CXCL8, IGF1, IGF1R, IGF2R, IGFBP7, IL2, PLK3, IL6ST, IL13, KIR3DL1, IL17A, PDX1, IRF4, IRF6, ITGA9, ITPR3, CLTC, MAGEA1, MCM7, CCN4, MDK, MST1R, MSX2, CDO1, CDKN3, CDKN2B, MUC6, GADD45B, CEACAM6, NCAM1, CDKN1A, NEU1, NF1, NFKB1, NGF, NM, NME2, CDK7, CDX1, MSH2, ABCC1, MITF, MAP3K1, MEN1, CFTR, MFAP1, SCGB2A1, MGMT, CXCL9, MLH1, MRC1, KMT2A, MME, MMP1, CETN1, MMP3, MMP7, MPO, IGBP1, IFNG, IFNA13, IFNA1, CYP1A2, ERCC1, CYP1A1, ESR2, ETV4, MECOM, CTSB, F2, F2R, FANCC, FAT1, CTNND1, FCGR3A, FCGR3B, FGFR1, FGFR4, NR5A2, EPS8, CYP19A1, CYP24A1, EEF1B2P2, DMBT1, DNMT3B, DPP4, E2F1, ECM1, EDN1, EDNRB, EFNB2, CYP27B1, DAP, EGI, EIF4E, ELAVL2, ELAVL1, MARK2, ENO1, GAST, FUT1, FUT2, HSPA5, ONECUT1, HOXA9, HOXB7, HOXD10, HRAS, HSF1, HSPA4, HSPD1, HMGA1, DNAJB1, HTR1A, ID3, CLDN7, CP, MAP3K8, COL11A2, HNF4A, HMGB1, FUT3, CSNK2B, GALNS, GATA3, GEM, GFER, GGT1, GJA1, GLUL, GNB3, HMBS, GPC1, GSK3B, GSTA3, GSTM3, HDAC1, NRG1, HHEX, NOTCH2, SLC11A2, NRAS, SLC3A2, TF, TFAP2A, TFF2, TFRC, TGFA, ATM, TGFB2, TGFB3, ATF3, TIAM1, TIMP1, TIMP3, ZFHX3, TNFRSF1A, DECR1, TPD52, TPH1, TEK, PPP1R11, TCTE3, SSTR2, SLC4A2, SLC22A2, SOD2, SPTB, SPTBN2, SRC, SSAV1, ST14, TCF21, STAT1, BMI1, STK11, SULT1A1, TAC1, SERPINA7, BCL9, TPT1, TTR, UBE2N, URI1, RECK, CUL4B, APOE, IKBKG, NCOA1, DYNLL1, BECN1, EED, TAM, RIPK1, APOB, TNFRSF6B, TNFRSF18, CES2, NRP1, CFLAR, APRT, NCOA3, UCHL1, WNT2, UCP2, SCGB1A1, UGT1A, UMPS, USF1, VDAC1, VEGFC, XPO1, MIA, YWHAZ, ARG1, SEMA3B, RAB7A, MFAP5, KMT2D, FASLG, SLC4A1, SKP2, YBX1, FBXW4, SERPINA1, CDH6, CDH1, CDK1, CDA, PKD2, PLA2G4A, PLAT, PLAU, PLG, PLK1, PMAIP1, SEPTIN4, PODXL, POU2F2, PPBP, PPL, ABCB4, ATP8B1, PER1, PAEP, NT5E, NTRK1, NTS, OPCML, ORM2, OSBP, P2RX7, SERPINB2, PECAM1, REG3A, PRKN, PAWR, PCNA, PDCD1, PDGFRB, PDHA1, PPP1R1A, PTPA, PPP5C, S100A2, RB1, REST, RMRP, RNASE3, RNF2, CAT, RPLP1, S100A6, RANBP2, S100A8, SAFB, SCT, CXCL5, SDC1, NAT2, SFRP4, RARB, RAC1, CD40LG, PROX1, PRKCI, CD40, MAPK7, MAPK8, MAPK13, MAP2K2, CD34, PRSS2, PVT1, PSMA3, PSMD10, CCNE1, PTGER1, PTK2, PTK6, PVR, ASS1

Drugs

(5R,5aR,8aR,9S)-9-[[4,6-O-[(R)-Ethylidene]-beta-D-glucopyranosyl]-oxy]-5-(4-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl}oxy)-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydroisobenzofuro[5,6-f][1,3]benzodioxol-6(5aH)-one, (R)-6-(2-fluorophenyl)-N-(3-(2-((2 -methoxyethyl)amino)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine dihydrochloride, 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl) bacteriochlorin, 5-amino-1-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-4-yl 1H-indol-2-yl ketone mono[(S)-2-hydroxysuccinate], Becatecarin, Bifunctional anti-PD-L1/TGFβ Trap fusion protein, Fibroblast growth factor receptor (FGFR) antagonist, Fibroblast growth factor receptor (FGFR) inhibitor, Fimaporfin, Ivosidenib ( TIBSOVO ), Porfimer sodium (for use with photodynamic therapy) ( PHOTOBARR, PHOTOFRIN ), sodium 2-hydroxylinoleate

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Description

Carcinomas of the biliary tract are aggressive malignancies, with 5-year survival of less than 10%. These carcinomas arise throughout the biliary tree and are anatomically classified as either intrahepatic or extrahepatic cholangiocarcinomas. Gallbladder carcinomas also arise from the biliary tree but have distinct natural histories compared to cholangiocarcinomas, suggesting different underlying tumor biology.

Cholangiocarcinoma incidence varies widely between geographic regions, reflecting the impact of different underlying etiologies. In endemic areas, liver fluke infections by O. viverrini and Clonorchis sinensis, both group I carcinogens, represent the major risk factor for cholangiocarcinomas. In nonendemic regions, other risk factors, including choledochal cysts (603003), hepatolithiasis, and primary sclerosing cholangitis (613806), are likely contributors (summary by Chan-on et al., 2013). Overall, the majority of patients lack such identifiable risk factors (summary by Jiao et al., 2013).

Pathogenesis

Hepatocellular carcinoma (HCC; 114550) and intrahepatic cholangiocarcinoma (ICC) differ markedly with regard to their morphology, metastatic potential, and responses to therapy. Seehawer et al. (2018) demonstrated that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 (601621) and Prdm5 (614161) as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Seehawer et al. (2018) concluded that their results provided insight into lineage commitment in liver tumorigenesis, and explained molecularly why common liver-damaging risk factors can lead to either HCC or ICC.

Molecular Genetics

Somatic Mutations

Jiao et al. (2013) performed exome sequencing of 32 intrahepatic cholangiocarcinomas and discovered frequent inactivating mutations in multiple chromatin-remodeling genes, including BAP1 (603089), ARID1A (603024), and PBRM1 (606083). Mutation in one of these genes occurred in almost half of the carcinomas sequenced. Jiao et al. (2013) also identified frequent mutations at reported hotspots in the IDH1 (147700) and IDH2 (147650) genes, encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 (191170) was the most frequently altered gene in a series of 9 gallbladder carcinomas.

Chan-on et al. (2013) profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing in 15 tumors and prevalence screening in 194 tumors identified recurrent somatic mutations in BAP1 and ARID1A. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related cholangiocarcinomas demonstrated statistically significant differences in mutation patterns: BAP1, IDH1, and IDH2 were more frequently mutated in non-O. viverrini cholangiocarcinomas, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in cholangiocarcinoma pathogenesis. Chan-on et al. (2013) concluded that these findings indicated that different etiologies may induce distinct somatic alterations, even within the same tumor type.