The role of molecular genetic factors in the development of cholangiocellular cancer: A review

Cover Page

Cite item

Full Text

Abstract

This article highlights the main inducers of cholangiocarcinogenesis. Data are presented on the study of gene mutations, the variations of which depending on the localization of biliary cancer may be different (FGFR2 – in intrahepatic PRKACA, PRKACB – cholangiocarcinoma in extrahepatic cholangiocarcinoma). Mutations in the KRAS, TP53, ARIAD1A genes are common in extrahepatic bile duct cancer. Epigenetic events such as DNA hypermethylation, histone modifications, chromatin remodeling, and disturbances in miRNA expression are considered. A number of epigenetic features, such as the presence of a TP53 gene mutation with hypermethylation of p14ARF, DAPK, and/or ASC, correlate with a more aggressive course of the disease. The role of the SOX17 gene in the development of drug resistance is highlighted. The study of molecular genetic features of extrahepatic bile duct cancer is an important aspect in understanding the pathogenesis of this type of tumor, reveals new prognostic and diagnostic markers of the disease. It is possible that in the future, as knowledge is accumulated, this will make it possible to individualize approaches to the treatment of this category of patients.

About the authors

Svetlana V. Chulkova

Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University

Author for correspondence.
Email: chulkova@mail.ru
ORCID iD: 0000-0003-4412-5019

Cand. Sci. (Med.)

Russian Federation, Moscow; Moscow

Vitaly I. Loginov

Research Institute of General Pathology and Pathophysiology

Email: werwolf2000@mail.ru

Cand. Sci. (Biol.)

Russian Federation, Moscow

Danil V. Podluzhny

Blokhin National Medical Research Center of Oncology

Email: danil-p@mail.ru
ORCID iD: 0000-0001-7375-3378

Cand. Sci. (Med.)

Russian Federation, Moscow

Angelina V. Egorova

Pirogov Russian National Research Medical University

Email: sapphir5@mail.ru
ORCID iD: 0000-0003-3904-8530

Cand. Sci. (Med.), Prof.

Russian Federation, Moscow

Dmitry G. Semichev

Pirogov Russian National Research Medical University

Email: dsemichev71@mail.ru
ORCID iD: 0000-0001-6148-8933

Resident

Russian Federation, Moscow

Irina A. Gladilina

Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University

Email: 0152@mail.ru
ORCID iD: 0000-0002-2481-0791

D. Sci. (Med.)

Russian Federation, Moscow; Moscow

Nikolai E. Kudashkin

Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University

Email: dr.kudashkin@mail.ru

Cand. Sci. (Med.)

Russian Federation, Moscow; Moscow

References

  1. Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer. 2019;19(1). doi: 10.1186/s12885-019-5391-0
  2. Fouassier L, Marzioni M, Afonso MB, et al. Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance. Liver Int. 2019;39(Suppl. 1):43-62. doi: 10.1111/liv.14102
  3. Гурмиков Б.Н., Коваленко Ю.А., Вишневский В.А., Чжао А.В. Молекулярно-генетические аспекты внутрипеченочного холангиоцеллюлярного рака: обзор литературы. Успехи молекулярной онкологии. 2019;6(1):37-43 [Gurmikov BN, Kovalenko YA, Vishnevsky VA, Chzhao AV. Molecular genetic aspects of intrahepatic cholangiocarcinoma:literature review. Advances in Molecular Oncology. 2019;6(1):37-43 (in Russian)]. doi: 10.17650/2313-805X-2019-6-1-37-43
  4. Мустафин Р.Н., Хуснутдинова Э.К. Эпигенетика канцерогенеза. Креативная хирургия и онкология. 2017;7(3):60-7 [Mustafin RN, Khusnutdinova EK. Epigenetics of carcinogenesis. Creative Surgery and Oncology. 2017;7(3):60-7 (in Russian)]. doi: 10.24060/2076-3093-2017-7-3-60-67
  5. Wang Y, Wan M, Zhou Q, et al. The Prognostic Role of SOCS3 and A20 in Human Cholangiocarcinoma. PLoS One. 2015;10(10):e0141165. doi: 10.1371/journal.pone.0141165
  6. Чулкова С.В., Маркина И.Г., Чернышева О.А., и др. Роль стволовых опухолевых клеток в развитии лекарственной резистентности меланомы. Российский биотерапевти- ческий журнал. 2019;18(2):6-14 [Chulkova SV, Markina IG, Chernysheva OA, et al. The role of tumor stem cells in the development of drug resistance of melanoma. Russian Journal of Biotherapy. 2019;18(2):6-14 (in Russian)]. doi: 10.17650/1726-9784-2019-18-2-6-14
  7. Jaiswal M, LaRusso N, Shapiro R, et al. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology. 2001;120(1):190-9. doi: 10.1053/gast.2001.20875
  8. Wei J, Wang B, Wang H, et al. Radiation-Induced Normal Tissue Damage: Oxidative Stress and Epigenetic Mechanisms. Oxid Med Cell Longev. 2019;2019:3010342. doi: 10.1155/2019/3010342
  9. Wu WR, Zhang R, Shi XD, et al. Notch1 is overexpressed in human intrahepatic cholangiocarcinoma and is associated with its proliferation, invasiveness and sensitivity to 5-fluorouracil in vitro. Oncol Rep. 2014;31:2515-24. doi: 10.3892/or.2014.3123
  10. Sirica A. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008;14(46):7033. doi: 10.3748/wjg.14.7033
  11. Pellat A, Vaquero J, Fouassier L. Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology. Hepatology. 2018;67(2):762-73. doi: 10.1002/hep.29350
  12. Lee H, Wang K, Johnson A, et al. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol. 2016;69(5):403-8. doi: 10.1136/jclinpath-2015-203394
  13. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-10. doi: 10.1038/ng.3375
  14. Ruzzenente A, Fassan M, Conci S, et al. Cholangiocarcinoma Heterogeneity Revealed by Multigene Mutational Profiling: Clinical and Prognostic Relevance in Surgically Resected Patients. Ann Surg Oncol. 2016;23(5):1699-707. doi: 10.1245/s10434-015-5046-6
  15. Roos E, Soer EC, Klompmaker S, et al. Crossing borders: A systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract. Crit Rev Oncol Hematol. 2019;140:8-16. doi: 10.1016/j.critrevonc.2019.05.011
  16. Brito AF, Abrantes AM, Encarnação JC, et al. Cholangiocarcinoma: from molecular biology to treatment. Med Oncol. 2015;32(11):245. doi: 10.1007/s12032-015-0692-x
  17. Kim BH, Cho NY, Shin SH, et al. CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma. Virchows Arch. 2009;455(4):343-51. doi: 10.1007/s00428-009-0829-4
  18. Sasaki M, Yamaguchi J, Itatsu K, et al. Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol. 2008;215(2):175-83. doi: 10.1002/path.2345
  19. Kongpetch S, Jusakul A, Ong CK, et al. Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways. Best Pract Res Clin Gastroenterol. 2015;29(2):233-44. doi: 10.1016/j.bpg.2015.02.002
  20. Castven D, Becker D, Czauderna C, et al. Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification. Int J Cancer. 2019;144(11):2782-94. doi: 10.1002/ijc.32026
  21. Xiaofang L, Kun T, Shaoping Y, et al. Correlation between promoter methylation of p14(ARF), TMS1/ASC, and DAPK, and p53 mutation with prognosis in cholangiocarcinoma. World J Surg Oncol. 2012;10:5. doi: 10.1186/1477-7819-10-5
  22. Andresen K, Boberg KM, Vedeld HM, et al. Novel target genes and a valid biomarker panel identified for cholangiocarcinoma. Epigenetics. 2012;7(11):1249-57. doi: 10.4161/epi.22191
  23. Merino-Azpitarte M, Lozano E, Perugorria MJ, et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol. 2017;67(1):72-83. doi: 10.1016/j.jhep.2017.02.017
  24. Jiang K, Centeno BA. Primary Liver Cancers, Part 2: Progression Pathways and Carcinogenesis. Cancer Control. 2018;25(1):1073274817744658. doi: 10.1177/1073274817744658
  25. Чулкова С.В., Рябчиков Д.А., Дудина И.А., и др. Перспективы использования миРНК в качестве диагностических и прогностических биомаркеров меланомы. Российский биотерапевтический журнал. 2019;18(4):51-6 [Chulkova SV, Ryabchikov DA, Dudina IA, et al. The prospects for the use of microRNA as diagnostic and prognostic melanoma biomarkers. Russian Journal of Biotherapy. 2019;18(4):51-6 (in Russian)]. doi: 10.17650/1726-9784-2019-18-4-51-56
  26. Рябчиков Д.А., Абдуллаева Э.И., Дудина И.А., и др. Роль микроРНК в канцерогенезе и прогнозе злокачественных новообразований молочной железы. Вестник Российского научного центра рентгенорадиологии Минздрава России. 2018;18(2):1-20 [Ryabchikov DA, Abdullaeva EI, Dudina IA, et al. The role of micro-RNA in cancerogenesis and breast cancer prognosis. Vestnik Rossijskogo nauchnogo centra rentgenoradiologii Minzdrava Rossii. 2018;18(2):1-20 (in Russian)].
  27. Selbach M, Schwanhausser B, Thierfelder N, et al. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455:58-63. doi: 10.1038/nature07228
  28. Braconi C, Huang N, Patel T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology. 2010;51:881-90. doi: 10.1002/hep.23381
  29. Рябчиков Д.А., Чулкова С.В., Талипов О.А., и др. Результаты анализа метилирования генов микроРНК в различных подтипах рака молочной железы. Онкогинекология. 2020;03(35):4-14 [Ryabchikov DA, Chulkova SV, Talipov OA, et al. Results of microRNA gene methylation analysis in different breast cancer subtypes. Oncogynecology. 2020;03(35):4-14 (in Russian)].
  30. Талипов О.А., Рябчиков Д.А., Чулкова С.В., и др. Метилирование генов супрессорных микроРНК при раке молочной железы. Онкогинекология. 2020;02(34):14-22 [Talipov OA, Ryabchikov DA, Chulkova SV, et al. Methylation Of Suppressor MicroRNA Genes In Breast Cancer. Oncogynecology. 2020;02(34):14-22 (in Russian)].
  31. Wei J, Wang B, Wang H, et al. Radiation-Induced Normal Tissue Damage: Oxidative Stress and Epigenetic Mechanisms. Oxid Med Cell Longev. 2019;2019:3010342. doi: 10.1155/2019/3010342
  32. Hill MA, Alexander WB, Guo B, et al. Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma. Cancer Res. 2018;78(16):4445-51. doi: 10.1158/0008-5472.CAN-17-1123
  33. Meng F, Wehbe-Janek H, Henson R, et al. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene. 2007;27(3):378-86. doi: 10.1038/sj.onc.1210648
  34. Fernández-Barrena M, Perugorria M, Banales J. Novel lncRNA T-UCR as a potential downstream driver of the Wnt/β-catenin pathway in hepatobiliary carcinogenesis. Gut. 2016;66(7):1177-8. doi: 10.1136/gutjnl-2016-312899
  35. Wangyang Z, Daolin J, Yi X, et al. NcRNAs and Cholangiocarcinoma. J Cancer. 2018;9(1):100-7. doi: 10.7150/jca.21785
  36. Moeini A, Sia D, Zhang Z, et al. Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity. J Hepatol. 2017;66(5):952-61. doi: 10.1016/j.jhep.2017.01.010
  37. O'Rourke CJ, Lafuente-Barquero J, Andersen JB. Epigenome Remodeling in Cholangiocarcinoma. Trends Cancer. 2019;5(6):335-50. doi: 10.1016/j.trecan.2019.05.002
  38. Weber J, Öllinger R, Friedrich M, et al. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. Proceedings of the National Academy of Sciences. 2015;112(45):13982-7. doi: 10.1073/pnas.1512392112
  39. Zhao S, Xu Y, Wu W, et al. ARID1A Variations in Cholangiocarcinoma: Clinical Significances and Molecular Mechanisms. Front Oncol. 2021;11:693295. doi: 10.3389/fonc.2021.693295
  40. Sasaki M, Nitta T, Sato Y, Nakanuma Y. Loss of ARID1A Expression Presents a Novel Pathway of Carcinogenesis in Biliary Carcinomas. Am J Clin Pathol. 2016;145(6):815-25. doi: 10.1093/ajcp/aqw071
  41. Morine Y, Shimada M, Iwahashi S, et al. Role of histone deacetylase expression in intrahepatic cholangiocarcinoma. Surgery. 2012;151(3):412-9. doi: 10.1016/j.surg.2011.07.038
  42. Gradilone S, Radtke B, Bogert P, et al. HDAC6 Inhibition Restores Ciliary Expression and Decreases Tumor Growth. Cancer Res. 2013;73(7):2259-70. doi: 10.1158/0008-5472.can-12-2938
  43. Pant K, Peixoto E, Richard S, Gradilone SA. Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma. Cells. 2020;9(3):780. doi: 10.3390/cells9030780
  44. Nakagawa S, Okabe H, Sakamoto Y, et al. Enhancer of Zeste Homolog 2 (EZH2) Promotes Progression of Cholangiocarcinoma Cells by Regulating Cell Cycle and Apoptosis. Ann Surg Oncol. 2013;20(S3):667-75. doi: 10.1245/s10434-013-3135-y

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Extrahepatic cholangiocarcinoma with ERBB2 S310F mutation. Hematoxylin-eosin staining [12].

Download (172KB)
Indexing metadata
3. Fig. 3. Scheme of the pathogenesis of cholangiocarcinoma with a mutation in the ARID1A gene [39].

Download (114KB)
Indexing metadata
4. Fig. 2. miRNA biogenesis [26].

Download (99KB)
Indexing metadata
5. Fig. 4. Consequences of HDAC6 overexpression [43].

Download (83KB)
Indexing metadata

Copyright (c) 2022 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies