Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press20410.17650/2313-805X-2019-6-1-37-43REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИMolecular genetic aspects of intrahepatic cholangiocarcinoma: literature reviewМолекулярно-генетические аспекты внутрипеченочного холангиоцеллюлярного рака: обзор литературыhttps://orcid.org/0000-0001-5958-3608GurmikovB. N.ГурмиковБ. Н.
Russian Federation

27 Bol’shaya Serpukhovskaya St., Moscow 117997.

Гурмиков Беслан Нуралиевич.

117997 Москва, ул. Большая Серпуховская, 27.

gurmikov@mail.ruKovalenkoYu. A.КоваленкоЮ. А.
Russian Federation

27 Bol’shaya Serpukhovskaya St., Moscow 117997.

117997 Москва, ул. Большая Серпуховская, 27.

VishnevskyV. A.ВишневскийВ. А.
Russian Federation

27 Bol’shaya Serpukhovskaya St., Moscow 117997.

117997 Москва, ул. Большая Серпуховская, 27.

ChzhaoA. V.ЧжаоА. В.
Russian Federation

27 Bol’shaya Serpukhovskaya St., Moscow 117997.

117997 Москва, ул. Большая Серпуховская, 27.

A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of RussiaНациональный медицинский исследовательский центр хирургии им. А.В. Вишневского Минздрава России150120196137432704201927042019Copyright ©; 2019, Gurmikov B.N., Kovalenko Y.A., Vishnevsky V.A., Chzhao A.V.Copyright ©; 2019, Гурмиков Б.Н., Коваленко Ю.А., Вишневский В.А., Чжао А.В.2019Gurmikov B.N., Kovalenko Y.A., Vishnevsky V.A., Chzhao A.V.Гурмиков Б.Н., Коваленко Ю.А., Вишневский В.А., Чжао А.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/204

The modern concept of therapy for intrahepatic cholangiocarcinoma including surgical treatment, must take into account the achievements of molecular biology and modern staging principles. A detailed understanding of the molecular genetic (genetic and epigenetic) disorders underlying the pathogenesis of cholangiocarcinoma is important, which will improve the results of surgical treatment and expand the possibilities of personalized (targeted) therapy. Based on new data on cholangiocarcinogenesis, molecular profiling of bile duct tumors may be most appropriate for the selection of treatment in cases refractory to standard therapy. Current potential target therapy targets include endothelial growth factor receptors, fibroblast growth factor, MET tyrosine kinase, PI3K/Akt/mTOR signaling pathway and isocitrate dehydrogenase mutation. The review considers the molecular-genetic aspects underlying the pathogenesis and modern principles of staging intrahepatic cholangiocarcinoma.

intrahepatic cholangiocarcinomamolecular genetic aspectstargeted therapystagingвнутрипеченочный холангиоцеллюлярный ракмолекулярно-генетические аспектытаргетная терапиястадированиеGrishechkina I.A., Viktorova I.A., Trukhan D.I., Kondratyeva N.A. Actual aspects of diagnostics of intrahepatic cholangiocarcinoma. Mezhdunarodnyy zhurnal prikladnykh i fundamental’nykh issledovaniy = International Journal of Applied and Fundamental Research 2016;11(1):61—5. (In Russ.).Гришечкина И.А., Викторова И.А., Трухан Д.И., Кондратьева Н.А. Актуальные аспекты диагностики внутрипеченочной холангиокарциномы. Международный журнал прикладных и фундаментальных исследований 2016;11(1):61—5.Rahnemai-Azar A.A., Weisbrod A.B., Dillhoff M. et al. Intrahepatic cholangiocarcinoma: current management and emerging therapies. Eхpert Rev Gasrtoenterol Hepatol 2017;11(5):439—49. DOI: 10.1080/17474124.2017.1309290. PMID:28317403.Buettner S., van Vugt J., Ijzermans J.N. Groot Koerkamp B. Intrahepatic cholangiocarcinoma: current perspectives. Onco Targets Ther 2017;10:1131-42. DOI: 10.2147/OTT.S93629. PMID: 28260927.Blechacz B.G., Feldman G.J. Tumors of the bile ducts, gallbladder, and ampulla. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease 2010;1:1171-6. DOI: https://doi.org/10.4143/crt.2015.497. PMID: 24140396.Jaiswal M., LaRusso N.F., Burgart L.J., Gores G.J. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxidedependent mechanism. Cancer Res 2000;60(1):184-90. PMID: 10646872.Park J., Tadlock L., Gores G.J., Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 1999;30:1128-33. DOI: 10.1002/hep.510300522. PMID: 10534331.Isomoto H., Kobayashi S., Werneburg N.W. et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005;42(6):1329-38. DOI:10.1002/hep.20966. PMID: 10534331.Rotin D.L. Cholangiocarcinoma today. Literary analytical review. Zlokachestvennye opukholi = Malignant tumors 2015;3(14):3—16. (In Russ.).Ротин Д.Л. Холангиоцеллюлярная карцинома сегодня. Литературный аналитический обзор. Злокачественные опухоли 2015;3(14):3-16. DOI: 10.18027/2224-5057-2015-3-3-16.Zender S., Nickeleit I., Wuestefeld T. et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 2013;23(6):784—95. DOI: 10.1016/j.ccr.2013.04.019. PMID: 23727022.Jinawath A., Akiyama Y., Sripa B., Yuasa Y. Dual blockade of the Hedgehog and ERK1/2 pathways coordinately decreases proliferation and survival of cholangiocarcinoma cells. J Cancer Res Clin Oncol 2007;133:271-8. DOI: https://doi.org/10.1007/s00432-006-0166-9. PMID: 17294242.Jinawath A., Akiyama Y., Sripa B., Yuasa Y. Dual blockade of the Hedgehog and ERK1/2 pathways coordinately decreases proliferation and survival of cholangiocarcinoma cells. J Cancer Res Clin Oncol 2007;133:271-8. DOI:https://doi.org/10.1007/s00432-006-0166-9. PMID: 17294242.Sirica A.E., Nathanson M.H., Gores G.J., Larusso N.F. Pathobiology of biliary epithelia and cholangiocarcinoma: proceedings of the Henry M. and Lillian Stratton Basic Research Single-Topic-Conference. Hepatology 2008;48(6):2040-6. DOI: 10.1002/hep.22623. PMID: 18855901.Boulter L., Guest R.V., Kendall T.J. et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest 2015;125(3): 1269-85. DOI: 10.1172/JCI76452. PMID: 25689248.Kiguchi K., Carbajal S., Chan K. et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001;61(19):6971—6. PMID:11585718.Chen M.H., Chiang K.C., Cheng C.T. et al. Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. Oncotarget 2014;5(9):2372-89. DOI: 10.18632/oncotarget.1706. PMID: 24796583.Ghouri Y.A., Mian I., Blechacz B. Cancer review: cholangiocarcinoma. J Carcinog 2015;14:1. DOI: 10.4103/1477-3163.151940. PMID: 25788866.Sia D., Tovar V., Moeini A., Llovet J.M. Intrahepatic cholangiocarcinoma: pathgenesis and rationale for molecular thera¬pies. Oncogene 2013;32(41):4861—70. DOI: 10.1038/onc.2012.617. PMID: 23318457.Xu R.F., Sun J.P., Zhang S.R. et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother 2011;65(1):22—6. DOI: 10.1016/j.biopha.2010.06.009. PMID: 21051183.Borger D.R., Tanabe K.K., Fan K.C. et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad based tumor genotyping. Oncologist 2012;17:72-9. DOI: 10.1634/theoncologist.2011-0386. PMID: 22180306.Kipp B.R., Voss J.S., Kerr S.E. et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol 2012;43:1552-8. DOI: 10.1016/j.humpath.2011.12.007. PMID: 22503487.Oishi N., Kumar M.R., Roessler S. et al. Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic2012;56(5):1792—803. DOI: 10.1002/hep.25890. PMID: 22707408.Nakaoka T., Saito Y., Saito H. Aberrant DNA methylation as a biomarker and therapeutic target of cholangiocarcinoma. Int J Mol Sci 2017;18(6):1111. DOI: 10.3390/ijms18061111. PMID: 28545228.Limpaiboon T., Khaenam, P., Chinnasri Р. et al. Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma. Cancer Lett 2005;217:213-9. DOI: 10.1016/j.canlet.2004.06.020. PMID: 15617839.Liu X.F., Kong F.M., Xu Z. et al. Promoter hypermethylation of deathassociated protein kinase gene in cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 2007;6:407-11. PMID: 17690039.Meng F., Wehbe-Janek H., Henson R. et al. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene 2008;27:378-86. DOI: 10.1038/sj.onc.1210648. PMID: 17621267.Pan X.P., Huang L.H., Wang X. MiR-370 functions as prognostic marker in patients with hepatocellular carcinoma. Eur Rev Med Pharmacol Sci 2017;21(16):3581-5. PMID: 28925487.Hibino S., Saito Y., Muramatsu T. et al. Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells. Oncogenesis 2014;3:104. DOI: 10.1038/oncsis.2014.17. PMID: 24861464.Uhm K.O., Lee E.S., Lee Y.M. et al. Aberrant promoter CpG islands methylation of tumor suppressor genes in cholangiocarcinoma. Oncol Res 2008;17(4):151 —7. PMID:18773859.Sirica A.E. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2012;9(1):44—54. DOI: 10.1038/nrgastro.2011.222. PMID: 22143274.Sirica A.E. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol 2008;14(46):7033—58. PMID: 19084911.Zhang Z., Oyesanya R.A., Campbell D.J. et al. Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy. Hepatology 2010;52(3):975—86. DOI: 10.1002/hep.23773. PMID: 20607690.Gruenberger B., Schueller J., Heubrandtner U. et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010;11(12):1142—8. DOI: 10.1016/S1470-2045(10)70247-3. PMID: 21071270.Lee J., Park S.H., Chang H.M. et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliarytract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012;13(2):181—8. DOI: 10.1016/S1470-2045(11)70301-1. PMID: 22192731.Moeini A., Sia D., Bardeesy N. et al. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res 2016;22(2): 291—300. DOI: 10.1158/1078-0432.CCR-14-3296. PMID: 26405193.Rizvi S., Khan S.H., Hallemeier Ch.L. et al. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 2018;15(2):95—111. DOI: 10.1038/nrclinonc.2017.157. PMID: 28994423.Borad M.J., Champion M.D, Egan J.B. et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 2014;10(2):e1004135. DOI: 10.1371/journal.pgen.1004135. PMID: 24550739.Soria J.C., Ohe Y., Vansteenkiste J. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25. DOI: 10.1056/NEJMoa1713137. PMID: 29151359.Miyamoto M., Ojima H., Iwasaki M. et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer 2011;105(1):131—8. DOI: 10.1038/bjc.2011.199. PMID: 21673683.Barat S., Bozko P., Chen X. et al. Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma. Mol Carcinog 2016;55(12):2037—50. DOI: 10.1002/mc.22449. PMID: 26757360.Pant S., Saleh M., Bendell J. et al. A phase I dose escalation study of oral c-MET inhibitor tivantinib(ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann Oncol 2014;25(7): 1416—21. DOI: 10.1093/annonc/mdu157. PMID: 24737778.Wang P., Dong Q., Zhang C. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 2013;32(25):3091—100. DOI: 10.1038/onc.2012.315. PMID: 22824796.Lim S.M., Yoo J.E., Lim K.H. et al. Rare Incidence of ROS1 Rearrangement in Cholangiocarcinoma. Cancer Res Treat 2016;49(1): 185-92. DOI: https://doi.org/10.4143/crt.2015.497. PMID: 27121721.Davare M.A., Saborowski A., Eide C.A. et al. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci USA 2013;110(48):19519—24. DOI: 10.1073/pnas.1319583110. PMID: 24218589.Xie D., Ren Z., Fan J., Gao Q. Genetic profiling of intrahepatic cholangiocarcinoma and its clinical implication in targeted therapy. Am J Cancer Res 2016;6(3):577-86. PMID: 27152236.Ewald F., Grabinski N., Grottke A. et al. Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma. Int J Cancer 2013;133(9):2065—76. DOI: 10.1002/ijc.28214. PMID: 23588885.Costello B.A., Borad M.J., Qi Y et al. Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Invest New Drugs 2014;32(4):710—6. DOI: 10.1007/s10637-014-0096-3. PMID: 24740268.Marcus K., Mattos C. Direct Attack on RAS: intramolecular communication and mutation-specific effects. Clin Cancer Res 2015;21(8):1810—8. DOI: 10.1158/1078-0432.CCR-14-2148. PMID: 25878362.Sia D., Hoshida Y., Villanueva A. et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013;144(4):829—40. DOI: 10.1053/j.gastro.2013.01.001. PMID: 23295441.Brierley J.D., Gospodarowicz M.K., Wittekind Ch. TNM classification of malignant tumours. Eighth Edition. 2017. Available at: http://www.hoofdhalskanker.info/wpavl/wp-content/uploads/TNM-Classification-of-Malignant-Tumours-8th-edition.pdf.