精准医疗时代重新审视胆管癌的诊治
|
摘要
胆管癌(cholangiocarcinoma,CCA)是一类相对少见的胆系恶性肿瘤.目前极其不良的预后源于对其分子发病机制认识不足和有效治疗方法的匮乏.精准医疗计划的提出和大量分析癌症基因组数据,有助于对肿瘤分子发病机制深入了解以及发现潜在治疗靶点.近年来研究证实肝内、外CCA无论流行病学、病因、分子发病机制、诊治方法和预后都存在较大差异,将CCA按肝内CCA、肝门部CCA和远端CCA分类并深入研究各型生物学特性是迈向精准个体化医疗战略中重要的第一步.相信随着基础和临床研究的深入,CCA各型组学信息的获得、整合和以此为据实施的精准靶向治疗,将改善患者预后,提高总生存率.
Cholangiocarcinoma(CCA) is a kind of relatively rare biliary system malignant tumor that has an extremely poor prognosis due to the lack of understanding of the molecular pathogenesis and the shortage of effective therapeutic methods. The adoption of precision medicine and cancer genomic profiling enhance our understanding of tumor molecular pathogenesis and can help identify potential therapeutic targets. Research has identified significant differences between intrahepatic and extrahepatic CCA, including epidemiology, etiology, molecular mechanisms, therapeutic methods and prognosis. The first important step towards personalized precise medicine strategy is classification of CCA and identification of the unique characteristics of each subtype. Hopefully, the acquisition and integration of omics information of CCA subtypes, and based on this, the development of effective targeted therapy will improve the prognosis and overall survival of patients.
Cholangiocarcinoma(CCA) is a kind of relatively rare biliary system malignant tumor that has an extremely poor prognosis due to the lack of understanding of the molecular pathogenesis and the shortage of effective therapeutic methods. The adoption of precision medicine and cancer genomic profiling enhance our understanding of tumor molecular pathogenesis and can help identify potential therapeutic targets. Research has identified significant differences between intrahepatic and extrahepatic CCA, including epidemiology, etiology, molecular mechanisms, therapeutic methods and prognosis. The first important step towards personalized precise medicine strategy is classification of CCA and identification of the unique characteristics of each subtype. Hopefully, the acquisition and integration of omics information of CCA subtypes, and based on this, the development of effective targeted therapy will improve the prognosis and overall survival of patients.
引文
1 Everhart JE,Ruhl CE.Burden of digestive diseases in the United States Part III:Liver,biliary tract,and pancreas.Gastroenterology 2009;136:1134-1144[PMID:19245868 DOI:10.1053/j.gastro.2009.02.038]
2 Khan SA,Davidson BR,Goldin RD,Heaton N,Karani J,Pereira SP,Rosenberg WM,Tait P,Taylor-Robinson SD,Thillainayagam AV,Thomas HC,Wasan H;British Society of Gastroenterology.Guidelines for the diagnosis and treatment of cholangiocarcinoma:an update.Gut 2012;61:1657-1669[PMID:22895392 DOI:10.1136/gutjnl-2011-301748]
3 Razumilava N,Gores GJ.Classification,diagnosis,and management of cholangiocarcinoma.Clin Gastroenterol Hepatol 2013;11:13-21.e1;quiz e3-e4[PMID:22982100 DOI:10.1016/j.cgh.2012.09.009]
4 Collins FS,Varmus H.A new initiative on precision medicine.N Engl J Med 2015;372:793-795[PMID:25635347 DOI:10.1056/NEJMp1500523]
5 Reardon S.Precision-medicine plan raises hopes.Nature 2015;517:540[PMID:25631425 DOI:10.1038/nature.2015.16774]
6 Tomaszewski JG,DeLaPena L,Gantz SB,Beranto DL,Woolery-Antill M,DiLorenzo K,Molenda J,Folts S.The immune system and cancer.Cancer Nurs 1995;18:313-328;quiz 329-330[PMID:7664259 DOI:10.1093/annonc/mdw324]
7 Byrling J,Andersson B,Andersson R,MarkoVarga G.Cholangiocarcinoma----current classification and challenges towards personalised medicine.Scand J Gastroenterol 2016;51:641-643[PMID:26806118 DOI:10.3109/00365521.2015.1127409]
8 Rizvi S,Borad MJ,Patel T,Gores GJ.Cholangiocarcinoma:molecular pathways and therapeutic opportunities.Semin Liver Dis 2014;34:456-464[PMID:25369307 DOI:10.1055/s-0034-1394144]
9 Cardinale V,Bragazzi MC,Carpino G,Torrice A,Fraveto A,Gentile R,Pasqualino V,Melandro F,Aliberti C,Bastianelli C,Brunelli R,Berloco PB,Gaudio E,Alvaro D.Cholangiocarcinoma:increasing burden of classifications.Hepatobiliary Surg Nutr 2013;2:272-280[PMID:24570958 DOI:10.3978/j.issn.2304-3881.2013.10.02]
10 Rizvi S,Gores GJ.Pathogenesis,diagnosis,and management of cholangiocarcinoma.Gastroenterology 2013;145:1215-1229[PMID:24140396 DOI:10.1053/j.gastro.2013.10.013]
11 Bergquist A,von Seth E.Epidemiology of cholangiocarcinoma.Best Pract Res Clin Gastroenterol 2015;29:221-232[PMID:25966423DOI:10.1016/j.bpg.2015.02.003]
12 Shaib Y,El-Serag HB.The epidemiology of cholangiocarcinoma.Semin Liver Dis 2004;24:115-125[PMID:15192785 DOI:10.1055/s-2004-828889]
13 Banales JM,Cardinale V,Carpino G,Marzioni M,Andersen JB,Invernizzi P,Lind GE,Folseraas T,Forbes SJ,Fouassier L,Geier A,Calvisi DF,Mertens JC,Trauner M,Benedetti A,Maroni L,Vaquero J,Macias RI,Raggi C,Perugorria MJ,Gaudio E,Boberg KM,Marin JJ,Alvaro D.Expert consensus document:Cholangiocarcinoma:current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma(ENS-CCA).Nat Rev Gastroenterol Hepatol 2016;13:261-280[PMID:27095655 DOI:10.1038/nrgastro.2016.51]
14 Sekiya S,Suzuki A.Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes.J Clin Invest 2012;122:3914-3918[PMID:23023701 DOI:10.1172/JCI63065]
15 Komuta M,Govaere O,Vandecaveye V,Akiba J,Van Steenbergen W,Verslype C,Laleman W,Pirenne J,Aerts R,Yano H,Nevens F,Topal B,Roskams T.Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology 2012;55:1876-1888[PMID:22271564 DOI:10.1002/hep.25595]
16 Putra J,de Abreu FB,Peterson JD,Pipas JM,Mody K,Amos CI,Tsongalis GJ,Suriawinata AA.Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing.Exp Mol Pathol 2015;99:240-244[PMID:26189129 DOI:10.1016/j.yexmp.2015.07.005]
17 Moeini A,Sia D,Bardeesy N,Mazzaferro V,Llovet JM.Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.Clin Cancer Res 2016;22:291-300[PMID:26405193DOI:10.1158/1078-0432.CCR-14-3296]
18 Lee H,Wang K,Johnson A,Jones DM,Ali SM,Elvin JA,Yelensky R,Lipson D,Miller VA,Stephens PJ,Javle M,Ross JS.Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets.J Clin Pathol2016;69:403-408[PMID:26500333 DOI:10.1136/jclinpath-2015-203394]
19 Borad MJ,Champion MD,Egan JB,Liang WS,Fonseca R,Bryce AH,McCullough AE,Barrett MT,Hunt K,Patel MD,Young SW,Collins JM,Silva AC,Condjella RM,Block M,McWilliams RR,Lazaridis KN,Klee EW,Bible KC,Harris P,Oliver GR,Bhavsar JD,Nair AA,Middha S,Asmann Y,Kocher JP,Schahl K,Kipp BR,Barr Fritcher EG,Baker A,Aldrich J,Kurdoglu A,Izatt T,Christoforides A,Cherni I,Nasser S,Reiman R,Phillips L,McDonald J,Adkins J,Mastrian SD,Placek P,Watanabe AT,Lobello J,Han H,Von Hoff D,Craig DW,Stewart AK,Carpten JD.Integrated genomic characterization reveals novel,therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.PLoS Genet2014;10:e1004135[PMID:24550739 DOI:10.1371/journal.pgen.1004135]
20 Graham RP,Barr Fritcher EG,Pestova E,Schulz J,Sitailo LA,Vasmatzis G,Murphy SJ,McWilliams RR,Hart SN,Halling KC,Roberts LR,Gores GJ,Couch FJ,Zhang L,Borad MJ,Kipp BR.Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma.Hum Pathol2014;45:1630-1638[PMID:24837095 DOI:10.1016/j.humpath.2014.03.014]
21 Ross JS,Wang K,Gay L,Al-Rohil R,Rand JV,Jones DM,Lee HJ,Sheehan CE,Otto GA,Palmer G,Yelensky R,Lipson D,Morosini D,Hawryluk M,Catenacci DV,Miller VA,Churi C,Ali S,Stephens PJ.New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.Oncologist 2014;19:235-242[PMID:24563076 DOI:10.1634/theoncologist.2013-0352]
22 Arai Y,Totoki Y,Hosoda F,Shirota T,Hama N,Nakamura H,Ojima H,Furuta K,Shimada K,Okusaka T,Kosuge T,Shibata T.Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.Hepatology 2014;59:1427-1434[PMID:24122810 DOI:10.1002/hep.26890]
23 Sia D,Losic B,Moeini A,Cabellos L,Hao K,Revill K,Bonal D,Miltiadous O,Zhang Z,Hoshida Y,Cornella H,Castillo-Martin M,Pinyol R,Kasai Y,Roayaie S,Thung SN,Fuster J,Schwartz ME,Waxman S,Cordon-Cardo C,Schadt E,Mazzaferro V,Llovet JM.Massive parallel sequencing uncovers actionable FGFR2-PPHLN1fusion and ARAF mutations in intrahepatic cholangiocarcinoma.Nat Commun 2015;6:6087[PMID:25608663 DOI:10.1038/ncomms7087]
24 Rizvi S,Yamada D,Hirsova P,Bronk SF,Werneburg NW,Krishnan A,Salim W,Zhang L,Trushina E,Truty MJ,Gores GJ.A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma.J Biol Chem 2016;291:8031-8047[PMID:26826125 DOI:10.1074/jbc.M115.698472]
25 Javle MM,Shroff RT,Zhu A,Sadeghi S,Choo S,Borad MJ,Lowery MA,El-Khoueiry A,Macarulla T,Philip PA,Oh DY,Cutsem EV,Yeh KH,Isaacs R,McGarry C,Sen S,Bekaii-Saab TS.A phase 2study of BGJ398 in patients(pts)with advanced or metastatic FGFR altered cholangiocarcinoma(CCA)who failed or are intolerant to platinumbased chemotherapy.J Clin Oncol 2016;abstr 335
26 Hall TG,Yu Y,Eathiraj S,Wang Y,Savage RE,Lapierre JM,Schwartz B,Abbadessa G.Preclinical Activity of ARQ 087,a Novel Inhibitor Targeting FGFR Dysregulation.PLoS One 2016;11:e0162594[PMID:27627808 DOI:10.1371/journal.pone.0162594]
27 Tan L,Wang J,Tanizaki J,Huang Z,Aref AR,Rusan M,Zhu SJ,Zhang Y,Ercan D,Liao RG,Capelletti M,Zhou W,Hur W,Kim N,Sim T,Gaudet S,Barbie DA,Yeh JR,Yun CH,Hammerman PS,Mohammadi M,J鋘ne PA,Gray NS.Development of covalent inhibitors that can overcome resistance to first-generation FGFRkinase inhibitors.Proc Natl Acad Sci USA 2014;111:E4869-E4877[PMID:25349422 DOI:10.1073/pnas.1403438111]
28 Bekaii-Saab T,Phelps MA,Li X,Saji M,Goff L,Kauh JS,O’Neil BH,Balsom S,Balint C,Liersemann R,Vasko VV,Bloomston M,Marsh W,Doyle LA,Ellison G,Grever M,Ringel MD,Villalona-Calero MA.Multi-institutional phase IIstudy of selumetinib in patients with metastatic biliary cancers.J Clin Oncol 2011;29:2357-2363[PMID:21519026 DOI:10.1200/JCO.2010.33.9473]
29 Churi CR,Shroff R,Wang Y,Rashid A,Kang HC,Weatherly J,Zuo M,Zinner R,Hong D,Meric-Bernstam F,Janku F,Crane CH,Mishra L,Vauthey JN,Wolff RA,Mills G,Javle M.Mutation profiling in cholangiocarcinoma:prognostic and therapeutic implications.PLoS One 2014;9:e115383[PMID:25536104 DOI:10.1371/journal.pone.0115383]
30 Zhu AX,Borger DR,Kim Y,Cosgrove D,Ejaz A,Alexandrescu S,Groeschl RT,Deshpande V,Lindberg JM,Ferrone C,Sempoux C,Yau T,Poon R,Popescu I,Bauer TW,Gamblin TC,Gigot JF,Anders RA,Pawlik TM.Genomic profiling of intrahepatic cholangiocarcinoma:refining prognosis and identifying therapeutic targets.Ann Surg Oncol 2014;21:3827-3834[PMID:24889489 DOI:10.1245/s10434-014-3828-x]
31 Kipp BR,Voss JS,Kerr SE,Barr Fritcher EG,Graham RP,Zhang L,Highsmith WE,Zhang J,Roberts LR,Gores GJ,Halling KC.Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.Hum Pathol 2012;43:1552-1558[PMID:22503487 DOI:10.1016/j.humpath.2011.12.007]
32 Borger DR,Tanabe KK,Fan KC,Lopez HU,Fantin VR,Straley KS,Schenkein DP,Hezel AF,Ancukiewicz M,Liebman HM,Kwak EL,Clark JW,Ryan DP,Deshpande V,Dias-Santagata D,Ellisen LW,Zhu AX,Iafrate AJ.Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.Oncologist2012;17:72-79[PMID:22180306 DOI:10.1634/theoncologist.2011-0386]
33 Wang P,Dong Q,Zhang C,Kuan PF,Liu Y,Jeck WR,Andersen JB,Jiang W,Savich GL,Tan TX,Auman JT,Hoskins JM,Misher AD,Moser CD,Yourstone SM,Kim JW,Cibulskis K,Getz G,Hunt HV,Thorgeirsson SS,Roberts LR,Ye D,Guan KL,Xiong Y,Qin LX,Chiang DY.Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.Oncogene 2013;32:3091-3100[PMID:22824796DOI:10.1038/onc.2012.315]
34 Goyal L,Govindan A,Sheth RA,Nardi V,Blaszkowsky LS,Faris JE,Clark JW,Ryan DP,Kwak EL,Allen JN,Murphy JE,Saha SK,Hong TS,Wo JY,Ferrone CR,Tanabe KK,Chong DQ,Deshpande V,Borger DR,Iafrate AJ,Bardeesy N,Zheng H,Zhu AX.Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase(IDH)Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma.Oncologist 2015;20:1019-1027[PMID:26245674 DOI:10.1634/theoncologist.2015-0210]
35 Nakamura H,Arai Y,Totoki Y,Shirota T,Elzawahry A,Kato M,Hama N,Hosoda F,Urushidate T,Ohashi S,Hiraoka N,Ojima H,Shimada K,Okusaka T,Kosuge T,Miyagawa S,Shibata T.Genomic spectra of biliary tract cancer.Nat Genet 2015;47:1003-1010[PMID:26258846DOI:10.1038/ng.3375]
36 Loilome W,Juntana S,Namwat N,Bhudhisawasdi V,Puapairoj A,Sripa B,Miwa M,Saya H,Riggins GJ,Yongvanit P.PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma.Int J Cancer 2011;129:34-44[PMID:20824711 DOI:10.1002/ijc.25646]
37 Oliver JR,Kushwah R,Hu J.Multiple roles of the epithelium-specific ETS transcription factor,ESE-1,in development and disease.Lab Invest2012;92:320-330[PMID:22157719 DOI:10.1038/labinvest.2011.186]
38 Gingras MC,Covington KR,Chang DK,Donehower LA,Gill AJ,Ittmann MM,Creighton CJ,Johns AL,Shinbrot E,Dewal N,Fisher WE;Australian Pancreatic Cancer Genome Initiative,Pilarsky C,Grützmann R,Overman MJ,Jamieson NB,Van Buren G 2nd,Drummond J,Walker K,Hampton OA,Xi L,Muzny DM,Doddapaneni H,Lee SL,Bellair M,Hu J,Han Y,Dinh HH,Dahdouli M,Samra JS,Bailey P,Waddell N,Pearson JV,Harliwong I,Wang H,Aust D,Oien KA,Hruban RH,Hodges SE,McElhany A,Saengboonmee C,Duthie FR,Grimmond SM,Biankin AV,Wheeler DA,Gibbs RA.Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNTDysregulation.Cell Rep 2016;14:907-919[PMID:26804919 DOI:10.1016/j.celrep.2015.12.005]
39 Yachida S,Wood LD,Suzuki M,Takai E,Totoki Y,Kato M,Luchini C,Arai Y,Nakamura H,Hama N,Elzawahry A,Hosoda F,Shirota T,Morimoto N,Hori K,Funazaki J,Tanaka H,Morizane C,Okusaka T,Nara S,Shimada K,Hiraoka N,Taniguchi H,Higuchi R,Oshima M,Okano K,Hirono S,Mizuma M,Arihiro K,Yamamoto M,Unno M,Yamaue H,Weiss MJ,Wolfgang CL,Furukawa T,Nakagama H,Vogelstein B,Kiyono T,Hruban RH,Shibata T.Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma.Cancer Cell 2016;29:229-240[PMID:26806338 DOI:10.1016/j.ccell.2015.12.012]
40 Fabris L,Cadamuro M,Moserle L,Dziura J,Cong X,Sambado L,Nardo G,Sonzogni A,Colledan M,Furlanetto A,Bassi N,Massani M,Cillo U,Mescoli C,Indraccolo S,Rugge M,Okolicsanyi L,Strazzabosco M.Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization.Hepatology 2011;54:890-899[PMID:21618579 DOI:10.1002/hep.24466]
41 Cadamuro M,Spagnuolo G,Sambado L,Indraccolo S,Nardo G,Rosato A,Brivio S,Caslini C,Stecca T,Massani M,Bassi N,Novelli E,Spirli C,Fabris L,Strazzabosco M.LowDose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.Cancer Res 2016;76:4775-4784[PMID:27328733 DOI:10.1158/0008-5472.CAN-16-0188]
42 Fingas CD,Bronk SF,Werneburg NW,Mott JL,Guicciardi ME,Cazanave SC,Mertens JC,Sirica AE,Gores GJ.Myofibroblast-derived PDGFBB promotes Hedgehog survival signaling in cholangiocarcinoma cells.Hepatology 2011;54:2076-2088[PMID:22038837 DOI:10.1002/hep.24588]
43 El Khatib M,Kalnytska A,Palagani V,Kossatz U,Manns MP,Malek NP,Wilkens L,Plentz RR.Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma.Hepatology 2013;57:1035-1045[PMID:23172661 DOI:10.1002/hep.26147]
44 Nomura R,Fujii H,Abe M,Sugo H,Ishizaki Y,Kawasaki S,Hino O.Mesothelin expression is a prognostic factor in cholangiocellular carcinoma.Int Surg 2013;98:164-169[PMID:23701154 DOI:10.9738/INTSURG-D-13-00001.1]
45 Leelawat K,Narong S,Udomchaiprasertkul W,Leelawat S,Tungpradubkul S.Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells.Cancer Cell Int 2009;9:3[PMID:19128511 DOI:10.1186/1475-2867-9-3]
46 Morton SD,Cadamuro M,Brivio S,Vismara M,Stecca T,Massani M,Bassi N,Furlanetto A,Joplin RE,Floreani A,Fabris L,Strazzabosco M.Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation.Oncotarget 2015;6:26052-26064[PMID:26296968 DOI:10.18632/oncotarget.4482]
47 Voss JS,Holtegaard LM,Kerr SE,Fritcher EG,Roberts LR,Gores GJ,Zhang J,Highsmith WE,Halling KC,Kipp BR.Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions.Hum Pathol 2013;44:1216-1222[PMID:23391413 DOI:10.1016/j.humpath.2012.11.006]
48 Andersen JB,Spee B,Blechacz BR,Avital I,Komuta M,Barbour A,Conner EA,Gillen MC,Roskams T,Roberts LR,Factor VM,Thorgeirsson SS.Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.Gastroenterology2012;142:1021-1031.e15[PMID:22178589 DOI:10.1053/j.gastro.2011.12.005]
49 Bridgewater J,Lopes A,Beare S,Duggan M,Lee D,Ricamara M,McEntee D,Sukumaran A,Wasan H,Valle JW.A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer:the ABC-04 study.BMC Cancer 2016;16:153[PMID:26912134 DOI:10.1186/s12885-016-2174-8]
50 Rizvi S,Gores GJ.Emerging molecular therapeutic targets for cholangiocarcinoma.J Hepatol 2017Apr 5.[Epub ahead of print][PMID:28389139 DOI:10.1016/j.jhep.2017.03.026]
2 Khan SA,Davidson BR,Goldin RD,Heaton N,Karani J,Pereira SP,Rosenberg WM,Tait P,Taylor-Robinson SD,Thillainayagam AV,Thomas HC,Wasan H;British Society of Gastroenterology.Guidelines for the diagnosis and treatment of cholangiocarcinoma:an update.Gut 2012;61:1657-1669[PMID:22895392 DOI:10.1136/gutjnl-2011-301748]
3 Razumilava N,Gores GJ.Classification,diagnosis,and management of cholangiocarcinoma.Clin Gastroenterol Hepatol 2013;11:13-21.e1;quiz e3-e4[PMID:22982100 DOI:10.1016/j.cgh.2012.09.009]
4 Collins FS,Varmus H.A new initiative on precision medicine.N Engl J Med 2015;372:793-795[PMID:25635347 DOI:10.1056/NEJMp1500523]
5 Reardon S.Precision-medicine plan raises hopes.Nature 2015;517:540[PMID:25631425 DOI:10.1038/nature.2015.16774]
6 Tomaszewski JG,DeLaPena L,Gantz SB,Beranto DL,Woolery-Antill M,DiLorenzo K,Molenda J,Folts S.The immune system and cancer.Cancer Nurs 1995;18:313-328;quiz 329-330[PMID:7664259 DOI:10.1093/annonc/mdw324]
7 Byrling J,Andersson B,Andersson R,MarkoVarga G.Cholangiocarcinoma----current classification and challenges towards personalised medicine.Scand J Gastroenterol 2016;51:641-643[PMID:26806118 DOI:10.3109/00365521.2015.1127409]
8 Rizvi S,Borad MJ,Patel T,Gores GJ.Cholangiocarcinoma:molecular pathways and therapeutic opportunities.Semin Liver Dis 2014;34:456-464[PMID:25369307 DOI:10.1055/s-0034-1394144]
9 Cardinale V,Bragazzi MC,Carpino G,Torrice A,Fraveto A,Gentile R,Pasqualino V,Melandro F,Aliberti C,Bastianelli C,Brunelli R,Berloco PB,Gaudio E,Alvaro D.Cholangiocarcinoma:increasing burden of classifications.Hepatobiliary Surg Nutr 2013;2:272-280[PMID:24570958 DOI:10.3978/j.issn.2304-3881.2013.10.02]
10 Rizvi S,Gores GJ.Pathogenesis,diagnosis,and management of cholangiocarcinoma.Gastroenterology 2013;145:1215-1229[PMID:24140396 DOI:10.1053/j.gastro.2013.10.013]
11 Bergquist A,von Seth E.Epidemiology of cholangiocarcinoma.Best Pract Res Clin Gastroenterol 2015;29:221-232[PMID:25966423DOI:10.1016/j.bpg.2015.02.003]
12 Shaib Y,El-Serag HB.The epidemiology of cholangiocarcinoma.Semin Liver Dis 2004;24:115-125[PMID:15192785 DOI:10.1055/s-2004-828889]
13 Banales JM,Cardinale V,Carpino G,Marzioni M,Andersen JB,Invernizzi P,Lind GE,Folseraas T,Forbes SJ,Fouassier L,Geier A,Calvisi DF,Mertens JC,Trauner M,Benedetti A,Maroni L,Vaquero J,Macias RI,Raggi C,Perugorria MJ,Gaudio E,Boberg KM,Marin JJ,Alvaro D.Expert consensus document:Cholangiocarcinoma:current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma(ENS-CCA).Nat Rev Gastroenterol Hepatol 2016;13:261-280[PMID:27095655 DOI:10.1038/nrgastro.2016.51]
14 Sekiya S,Suzuki A.Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes.J Clin Invest 2012;122:3914-3918[PMID:23023701 DOI:10.1172/JCI63065]
15 Komuta M,Govaere O,Vandecaveye V,Akiba J,Van Steenbergen W,Verslype C,Laleman W,Pirenne J,Aerts R,Yano H,Nevens F,Topal B,Roskams T.Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology 2012;55:1876-1888[PMID:22271564 DOI:10.1002/hep.25595]
16 Putra J,de Abreu FB,Peterson JD,Pipas JM,Mody K,Amos CI,Tsongalis GJ,Suriawinata AA.Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing.Exp Mol Pathol 2015;99:240-244[PMID:26189129 DOI:10.1016/j.yexmp.2015.07.005]
17 Moeini A,Sia D,Bardeesy N,Mazzaferro V,Llovet JM.Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.Clin Cancer Res 2016;22:291-300[PMID:26405193DOI:10.1158/1078-0432.CCR-14-3296]
18 Lee H,Wang K,Johnson A,Jones DM,Ali SM,Elvin JA,Yelensky R,Lipson D,Miller VA,Stephens PJ,Javle M,Ross JS.Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets.J Clin Pathol2016;69:403-408[PMID:26500333 DOI:10.1136/jclinpath-2015-203394]
19 Borad MJ,Champion MD,Egan JB,Liang WS,Fonseca R,Bryce AH,McCullough AE,Barrett MT,Hunt K,Patel MD,Young SW,Collins JM,Silva AC,Condjella RM,Block M,McWilliams RR,Lazaridis KN,Klee EW,Bible KC,Harris P,Oliver GR,Bhavsar JD,Nair AA,Middha S,Asmann Y,Kocher JP,Schahl K,Kipp BR,Barr Fritcher EG,Baker A,Aldrich J,Kurdoglu A,Izatt T,Christoforides A,Cherni I,Nasser S,Reiman R,Phillips L,McDonald J,Adkins J,Mastrian SD,Placek P,Watanabe AT,Lobello J,Han H,Von Hoff D,Craig DW,Stewart AK,Carpten JD.Integrated genomic characterization reveals novel,therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.PLoS Genet2014;10:e1004135[PMID:24550739 DOI:10.1371/journal.pgen.1004135]
20 Graham RP,Barr Fritcher EG,Pestova E,Schulz J,Sitailo LA,Vasmatzis G,Murphy SJ,McWilliams RR,Hart SN,Halling KC,Roberts LR,Gores GJ,Couch FJ,Zhang L,Borad MJ,Kipp BR.Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma.Hum Pathol2014;45:1630-1638[PMID:24837095 DOI:10.1016/j.humpath.2014.03.014]
21 Ross JS,Wang K,Gay L,Al-Rohil R,Rand JV,Jones DM,Lee HJ,Sheehan CE,Otto GA,Palmer G,Yelensky R,Lipson D,Morosini D,Hawryluk M,Catenacci DV,Miller VA,Churi C,Ali S,Stephens PJ.New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.Oncologist 2014;19:235-242[PMID:24563076 DOI:10.1634/theoncologist.2013-0352]
22 Arai Y,Totoki Y,Hosoda F,Shirota T,Hama N,Nakamura H,Ojima H,Furuta K,Shimada K,Okusaka T,Kosuge T,Shibata T.Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.Hepatology 2014;59:1427-1434[PMID:24122810 DOI:10.1002/hep.26890]
23 Sia D,Losic B,Moeini A,Cabellos L,Hao K,Revill K,Bonal D,Miltiadous O,Zhang Z,Hoshida Y,Cornella H,Castillo-Martin M,Pinyol R,Kasai Y,Roayaie S,Thung SN,Fuster J,Schwartz ME,Waxman S,Cordon-Cardo C,Schadt E,Mazzaferro V,Llovet JM.Massive parallel sequencing uncovers actionable FGFR2-PPHLN1fusion and ARAF mutations in intrahepatic cholangiocarcinoma.Nat Commun 2015;6:6087[PMID:25608663 DOI:10.1038/ncomms7087]
24 Rizvi S,Yamada D,Hirsova P,Bronk SF,Werneburg NW,Krishnan A,Salim W,Zhang L,Trushina E,Truty MJ,Gores GJ.A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma.J Biol Chem 2016;291:8031-8047[PMID:26826125 DOI:10.1074/jbc.M115.698472]
25 Javle MM,Shroff RT,Zhu A,Sadeghi S,Choo S,Borad MJ,Lowery MA,El-Khoueiry A,Macarulla T,Philip PA,Oh DY,Cutsem EV,Yeh KH,Isaacs R,McGarry C,Sen S,Bekaii-Saab TS.A phase 2study of BGJ398 in patients(pts)with advanced or metastatic FGFR altered cholangiocarcinoma(CCA)who failed or are intolerant to platinumbased chemotherapy.J Clin Oncol 2016;abstr 335
26 Hall TG,Yu Y,Eathiraj S,Wang Y,Savage RE,Lapierre JM,Schwartz B,Abbadessa G.Preclinical Activity of ARQ 087,a Novel Inhibitor Targeting FGFR Dysregulation.PLoS One 2016;11:e0162594[PMID:27627808 DOI:10.1371/journal.pone.0162594]
27 Tan L,Wang J,Tanizaki J,Huang Z,Aref AR,Rusan M,Zhu SJ,Zhang Y,Ercan D,Liao RG,Capelletti M,Zhou W,Hur W,Kim N,Sim T,Gaudet S,Barbie DA,Yeh JR,Yun CH,Hammerman PS,Mohammadi M,J鋘ne PA,Gray NS.Development of covalent inhibitors that can overcome resistance to first-generation FGFRkinase inhibitors.Proc Natl Acad Sci USA 2014;111:E4869-E4877[PMID:25349422 DOI:10.1073/pnas.1403438111]
28 Bekaii-Saab T,Phelps MA,Li X,Saji M,Goff L,Kauh JS,O’Neil BH,Balsom S,Balint C,Liersemann R,Vasko VV,Bloomston M,Marsh W,Doyle LA,Ellison G,Grever M,Ringel MD,Villalona-Calero MA.Multi-institutional phase IIstudy of selumetinib in patients with metastatic biliary cancers.J Clin Oncol 2011;29:2357-2363[PMID:21519026 DOI:10.1200/JCO.2010.33.9473]
29 Churi CR,Shroff R,Wang Y,Rashid A,Kang HC,Weatherly J,Zuo M,Zinner R,Hong D,Meric-Bernstam F,Janku F,Crane CH,Mishra L,Vauthey JN,Wolff RA,Mills G,Javle M.Mutation profiling in cholangiocarcinoma:prognostic and therapeutic implications.PLoS One 2014;9:e115383[PMID:25536104 DOI:10.1371/journal.pone.0115383]
30 Zhu AX,Borger DR,Kim Y,Cosgrove D,Ejaz A,Alexandrescu S,Groeschl RT,Deshpande V,Lindberg JM,Ferrone C,Sempoux C,Yau T,Poon R,Popescu I,Bauer TW,Gamblin TC,Gigot JF,Anders RA,Pawlik TM.Genomic profiling of intrahepatic cholangiocarcinoma:refining prognosis and identifying therapeutic targets.Ann Surg Oncol 2014;21:3827-3834[PMID:24889489 DOI:10.1245/s10434-014-3828-x]
31 Kipp BR,Voss JS,Kerr SE,Barr Fritcher EG,Graham RP,Zhang L,Highsmith WE,Zhang J,Roberts LR,Gores GJ,Halling KC.Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.Hum Pathol 2012;43:1552-1558[PMID:22503487 DOI:10.1016/j.humpath.2011.12.007]
32 Borger DR,Tanabe KK,Fan KC,Lopez HU,Fantin VR,Straley KS,Schenkein DP,Hezel AF,Ancukiewicz M,Liebman HM,Kwak EL,Clark JW,Ryan DP,Deshpande V,Dias-Santagata D,Ellisen LW,Zhu AX,Iafrate AJ.Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.Oncologist2012;17:72-79[PMID:22180306 DOI:10.1634/theoncologist.2011-0386]
33 Wang P,Dong Q,Zhang C,Kuan PF,Liu Y,Jeck WR,Andersen JB,Jiang W,Savich GL,Tan TX,Auman JT,Hoskins JM,Misher AD,Moser CD,Yourstone SM,Kim JW,Cibulskis K,Getz G,Hunt HV,Thorgeirsson SS,Roberts LR,Ye D,Guan KL,Xiong Y,Qin LX,Chiang DY.Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.Oncogene 2013;32:3091-3100[PMID:22824796DOI:10.1038/onc.2012.315]
34 Goyal L,Govindan A,Sheth RA,Nardi V,Blaszkowsky LS,Faris JE,Clark JW,Ryan DP,Kwak EL,Allen JN,Murphy JE,Saha SK,Hong TS,Wo JY,Ferrone CR,Tanabe KK,Chong DQ,Deshpande V,Borger DR,Iafrate AJ,Bardeesy N,Zheng H,Zhu AX.Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase(IDH)Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma.Oncologist 2015;20:1019-1027[PMID:26245674 DOI:10.1634/theoncologist.2015-0210]
35 Nakamura H,Arai Y,Totoki Y,Shirota T,Elzawahry A,Kato M,Hama N,Hosoda F,Urushidate T,Ohashi S,Hiraoka N,Ojima H,Shimada K,Okusaka T,Kosuge T,Miyagawa S,Shibata T.Genomic spectra of biliary tract cancer.Nat Genet 2015;47:1003-1010[PMID:26258846DOI:10.1038/ng.3375]
36 Loilome W,Juntana S,Namwat N,Bhudhisawasdi V,Puapairoj A,Sripa B,Miwa M,Saya H,Riggins GJ,Yongvanit P.PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma.Int J Cancer 2011;129:34-44[PMID:20824711 DOI:10.1002/ijc.25646]
37 Oliver JR,Kushwah R,Hu J.Multiple roles of the epithelium-specific ETS transcription factor,ESE-1,in development and disease.Lab Invest2012;92:320-330[PMID:22157719 DOI:10.1038/labinvest.2011.186]
38 Gingras MC,Covington KR,Chang DK,Donehower LA,Gill AJ,Ittmann MM,Creighton CJ,Johns AL,Shinbrot E,Dewal N,Fisher WE;Australian Pancreatic Cancer Genome Initiative,Pilarsky C,Grützmann R,Overman MJ,Jamieson NB,Van Buren G 2nd,Drummond J,Walker K,Hampton OA,Xi L,Muzny DM,Doddapaneni H,Lee SL,Bellair M,Hu J,Han Y,Dinh HH,Dahdouli M,Samra JS,Bailey P,Waddell N,Pearson JV,Harliwong I,Wang H,Aust D,Oien KA,Hruban RH,Hodges SE,McElhany A,Saengboonmee C,Duthie FR,Grimmond SM,Biankin AV,Wheeler DA,Gibbs RA.Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNTDysregulation.Cell Rep 2016;14:907-919[PMID:26804919 DOI:10.1016/j.celrep.2015.12.005]
39 Yachida S,Wood LD,Suzuki M,Takai E,Totoki Y,Kato M,Luchini C,Arai Y,Nakamura H,Hama N,Elzawahry A,Hosoda F,Shirota T,Morimoto N,Hori K,Funazaki J,Tanaka H,Morizane C,Okusaka T,Nara S,Shimada K,Hiraoka N,Taniguchi H,Higuchi R,Oshima M,Okano K,Hirono S,Mizuma M,Arihiro K,Yamamoto M,Unno M,Yamaue H,Weiss MJ,Wolfgang CL,Furukawa T,Nakagama H,Vogelstein B,Kiyono T,Hruban RH,Shibata T.Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma.Cancer Cell 2016;29:229-240[PMID:26806338 DOI:10.1016/j.ccell.2015.12.012]
40 Fabris L,Cadamuro M,Moserle L,Dziura J,Cong X,Sambado L,Nardo G,Sonzogni A,Colledan M,Furlanetto A,Bassi N,Massani M,Cillo U,Mescoli C,Indraccolo S,Rugge M,Okolicsanyi L,Strazzabosco M.Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization.Hepatology 2011;54:890-899[PMID:21618579 DOI:10.1002/hep.24466]
41 Cadamuro M,Spagnuolo G,Sambado L,Indraccolo S,Nardo G,Rosato A,Brivio S,Caslini C,Stecca T,Massani M,Bassi N,Novelli E,Spirli C,Fabris L,Strazzabosco M.LowDose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.Cancer Res 2016;76:4775-4784[PMID:27328733 DOI:10.1158/0008-5472.CAN-16-0188]
42 Fingas CD,Bronk SF,Werneburg NW,Mott JL,Guicciardi ME,Cazanave SC,Mertens JC,Sirica AE,Gores GJ.Myofibroblast-derived PDGFBB promotes Hedgehog survival signaling in cholangiocarcinoma cells.Hepatology 2011;54:2076-2088[PMID:22038837 DOI:10.1002/hep.24588]
43 El Khatib M,Kalnytska A,Palagani V,Kossatz U,Manns MP,Malek NP,Wilkens L,Plentz RR.Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma.Hepatology 2013;57:1035-1045[PMID:23172661 DOI:10.1002/hep.26147]
44 Nomura R,Fujii H,Abe M,Sugo H,Ishizaki Y,Kawasaki S,Hino O.Mesothelin expression is a prognostic factor in cholangiocellular carcinoma.Int Surg 2013;98:164-169[PMID:23701154 DOI:10.9738/INTSURG-D-13-00001.1]
45 Leelawat K,Narong S,Udomchaiprasertkul W,Leelawat S,Tungpradubkul S.Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells.Cancer Cell Int 2009;9:3[PMID:19128511 DOI:10.1186/1475-2867-9-3]
46 Morton SD,Cadamuro M,Brivio S,Vismara M,Stecca T,Massani M,Bassi N,Furlanetto A,Joplin RE,Floreani A,Fabris L,Strazzabosco M.Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation.Oncotarget 2015;6:26052-26064[PMID:26296968 DOI:10.18632/oncotarget.4482]
47 Voss JS,Holtegaard LM,Kerr SE,Fritcher EG,Roberts LR,Gores GJ,Zhang J,Highsmith WE,Halling KC,Kipp BR.Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions.Hum Pathol 2013;44:1216-1222[PMID:23391413 DOI:10.1016/j.humpath.2012.11.006]
48 Andersen JB,Spee B,Blechacz BR,Avital I,Komuta M,Barbour A,Conner EA,Gillen MC,Roskams T,Roberts LR,Factor VM,Thorgeirsson SS.Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.Gastroenterology2012;142:1021-1031.e15[PMID:22178589 DOI:10.1053/j.gastro.2011.12.005]
49 Bridgewater J,Lopes A,Beare S,Duggan M,Lee D,Ricamara M,McEntee D,Sukumaran A,Wasan H,Valle JW.A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer:the ABC-04 study.BMC Cancer 2016;16:153[PMID:26912134 DOI:10.1186/s12885-016-2174-8]
50 Rizvi S,Gores GJ.Emerging molecular therapeutic targets for cholangiocarcinoma.J Hepatol 2017Apr 5.[Epub ahead of print][PMID:28389139 DOI:10.1016/j.jhep.2017.03.026]