A. Amirkulova^1,2, G. Derbissalina², N. Shanazarov¹, Zh. Bekbergenova²

1.«Hospital of the Medical Center of the Administration of the President of the Republic of Kazakhstan» RSE on REM, Astana, the Republic of Kazakhstan;
2. «Astana Medical University» NJSC, Astana, the Republic of Kazakhstan

DOI: https://www.doi.org/10.52532/2521-6414-2024-1-71-46-50

UDC: 616.36-006:575.224.2

Year: 2024 issure: 71 number: 1 pages: 46-50

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ABSTRACT

Relevance: Hepatocellular carcinoma (HCC) is the most common form of primary liver malignancy. This form of liver cancer is characterized by rapid progression and poor survival prognosis. Understanding the genetic mechanisms that underlie HCC is of great importance for developing new diagnostic and therapeutic approaches.
The study aimed to the genetic factors in the development of hepatocellular carcinoma.
Methods: This review used various sources of literature, including scientific articles and reviews. We reviewed the results of scientific and clinical studies published in 2018-2023 and indexed in the PubMed, Cochrane library, Scopus and Web of Science databases, using the keywords “hepatocellular carcinoma,” “genes,” and “genetic predictors.” Inclusion of articles in the review was based on their content and relevance to the research topic.
Results: Various genes associated with hepatocellular carcinoma were analyzed, including genes frequently mutated in HCC, as well as genes that play a role in the regulation of cell growth, apoptosis, metastasis, and invasion. Epigenetic changes such as DNA methylation and chromatin modifications have been investigated. The roles of microRNAs, long non-coding RNAs, circulating microparticles and other biomarkers in the diagnosis and prognosis of HCC were also reviewed.
Conclusion: The materials and methods used in this review allowed us to cover a wide range of genes and molecular mechanisms associated with hepatocellular carcinoma. Understanding these mechanisms plays an important role in the development of new diagnostic and therapeutic approaches to combat this dangerous form of liver cancer. Further research in this area will help expand our knowledge base and improve the HCC treatment.
Keywords: hepatocellular carcinoma, liver cancer, gene, risk factor.

List of sources used:

1. Asrani S.K., Devarbhavi H., Eaton J., Kamath P.S. Burden of liver diseases in the world // J. Hepatol. – 2019. – Vol. 70(1). – P. 151-171. https://doi.org/10.1016/j.jhep.2018.09.014
2. Fitzmaurice C., Abate D., Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study // JAMA Oncol. – 2019. – Vol. 5(12). – P. 1749-1768. https://doi.org/10.1001/jamaoncol.2019.2996
3. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries // Cancer J. Clin. – 2021. – Vol. 71(3). – P. 209-249. https://doi.org/10.3322/caac.21660
4. Foerster F, Gairing SJ, Müller L, Galle PR. NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options // J. Hepatol. – 2022. – Vol. 76(2). – P. 446-457. https://doi.org/10.1016/j.jhep.2021.09.007
5. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends.// J Hepatol.- 2020.- Vol. 72(2). – P.250–61. https://doi.org/10.1016/j.jhep.2019.08.025.
6. Sung H., Ferlay J., Siegel RL., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countriesь // CA Cancer J Clin. – 2021. – Vol. 71. – P. 209-249 https://doi.org/10.1111/liv.15251
7. Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. // Gastroenterology. – 2019. – Vol. 156(2). – P. 477-491. https://doi.org/10.1053/j.gastro.2018.08.065
8. Huang D.Q., El-Serag H.B., Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention // Nat. Rev. Gastroenterol. Hepatol. – 2021. – Vol. 18(4). – P. 223-238. https://doi.org/10.1038/s41575-020-00381-6
9. Chang Y., Liu B., Niu H., Wang Z., Xia S., Li H. Value of anti-p53 antibody as a biomarker for hepatocellular carcinoma. Evidence from a meta-analysis // Medicine (Baltimore). – 2020. – Vol. 99(34). ­– P. e21887. https://doi.org/10.1097/MD.0000000000021887
10. Huo J., Wu L., Zang Y. Development and validation of a CTNNB1-associated metabolic prognostic model for hepatocellular carcinoma // J. Cell. Mol. Med. – 2021. – Vol.25(2). – P. 1151-1165. https://doi.org/10.1111/jcmm.16181
11. Xiao X., Mo H., Tu K. CTNNB1 mutation suppresses infiltration of immune cells in hepatocellular carcinoma through miRNA-mediated regulation of chemokine expression // Int. Immunopharmacol. – 2020. – Vol. 89 (Pt. A). – Art. no. 107043. https://doi.org/10.1016/j.intimp.2020.107043
12. Ambrozkiewicz F., Trailin A., Červenková L., Vaclavikova R., Hanicinec V., Allah M.A.O., Palek R., Třeška V., Daum O., Tonar Z., Liška V., Hemminki K. CTNNB1 mutations, TERT polymorphism and CD8+ cell densities in resected hepatocellular carcinoma are associated with longer time to recurrence // BMC Cancer. – 2022. – Vol. 22(1). – P. 884. https://doi.org/10.1186/s12885-022-09989-0
13. Buch S., Innes H., Lutz P.L., Nischalke H.D., Marquardt J..U, Fischer J., Weiss K.H., Rosendahl J., Marot A., Krawczyk M., Casper M., Lammert F., Eyer F., Vogel A., Marhenke S., von Felden J., Sharma R., Atkinson S.R., McQuillin A., Nattermann J., Schafmayer C., Franke A., Strassburg C., Rietschel M., Altmann H., Sulk S., Thangapandi V.R., Brosch M., Lackner C., Stauber R.E, Canbay A., Link A., Reiberger T., Mandorfer M., Semmler G., Scheiner B., Datz C., Romeo S., Ginanni Corradini S., Irving W.L., Morling J.R., Guha I.N., Barnes E., Ansari M.A., Quistrebert J., Valenti L., Müller S.A., Morgan M.Y., Dufour J.F., Trebicka J., Berg T., Deltenre P., Mueller S., Hampe J., Stickel F. Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study // Gut. – 2023. – Vol. 72(2). – P. 381-391. https://doi.org/10.1136/gutjnl-2022-327196
14. Seif Eldin W.R., Saad E.A., Monier A., Elshazli R.M. Association of TERT (rs2736098 and rs2736100) genetic variants with elevated risk of hepatocellular carcinoma: a retrospective case-control study // Sci. Rep. – 2023. – Vol. 13(1). – P. 18382. https://doi.org/10.1038/s41598-023-45716-w
15. Zhao Y., Yang B., Chen D., Zhou X., Wang M., Jiang J., Wei L., Chen Z. Combined identification of ARID1A, CSMD1, and SENP3 as effective prognostic biomarkers for hepatocellular carcinoma // Aging (Albany NY). – 2021. – Vol. 13(3). – P. 4696-4712. https://doi.org/10.18632/aging.202586
16. Feng Y., Tang X., Li C., Su Y., Wang X., Li N., Zhang A., Jiang F., Wu C. ARID1A is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma // Can. J. Gastroenterol. Hepatol. – 2022. – Vol. 2022. – Art. no. 3163955. https://doi.org/10.1155/2022/3163955
17. Zhang S., Zhou Y.F., Cao J., Burley S.K., Wang H.Y., Zheng X.F.S. mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma // Cancer Res. – 2021. – Vol. 81(22). – P. 5652-5665. https://doi.org/10.1158/0008-5472.CAN-21-0206
18. Wang W., Liu P., Lavrijsen M., Li S., Zhang R., Li S., van de Geer W.S., van de Werken H.J.G., Peppelenbosch M.P., Smits R. Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines // Sci. Rep. – 2021. – Vol. 11. – Art. no. 7470 (2021). https://doi.org/10.1038/s41598-021-87091-4
19. Qiao Y., Wang J., Karagoz E., Liang B., Song X., Shang R., Evert K., Xu M., Che L., Evert M., Calvisi D.F., Tao J., Wang B., Monga S.P., Chen X. Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact β-Catenin but Not Notch Cascade in Mice // Hepatology. – 2019. – Vol. 70(6). – P. 2003-2017. https://doi.org/10.1002/hep.30556
20. Cuzziol C.I., Castanhole-Nunes M.M.U., Pavarino É.C., Goloni-Bertollo E.M. MicroRNAs as regulators of VEGFA and NFE2L2 in cancer // Gene. – 2020. – Vol. 759. – Art. no. 144994. https://doi.org/10.1016/j.gene.2020.144994
21. Fu J., Wang T., Zhai X., Xiao X. Primary hepatocellular adenoma due to biallelic HNF1A mutations and its co-occurrence with MODY 3: case-report and review of the literature // Endocrine. – 2020. – Vol. 67(3). – P. 544-551. https://doi.org/10.1007/s12020-019-02138-x
22. Gupta M., Chandan K., Sarwat M. Role of microRNA and Long Non-Coding RNA in Hepatocellular Carcinoma // Curr. Pharm. Des. – 2020. – Vol. 26(4). – P. 415-428. https://doi.org/10.2174/1381612826666200115093835
23. Oura K., Morishita A., Masaki T. Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review // Int. J. Mol. Sci. – 2020. – Vol. 21(21). – Art. no. 8362. https://doi.org/10.3390/ijms21218362
24. Zhou Y., Liu F., Ma C., Cheng Q. Involvement of microRNAs and their potential diagnostic, therapeutic, and prognostic role in hepatocellular carcinoma // J. Clin. Lab. Anal. – 2022. – Vol. (10). – Art. no. e24673. https://doi.org/10.1002/jcla.24673
25. Shi T., Morishita A., Kobara H., Masaki T. The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment // Int. J. Mol. Sci. – 2021. – Vol. 22(19). – Art. no. 10630. https://doi.org/10.3390/ijms221910630
26. Song Z., Yu Z., Chen L., Zhou Z., Zou Q., Liu Y. MicroRNA-1181 supports the growth of hepatocellular carcinoma by repressing AXIN1 // Biomed Pharmacother. – 2019. – Vol. 119. – Art. no.109397. https://doi.org/10.1016/j.biopha.2019.109397
27. Krutsenko Y., Singhi A.D., Monga S.P. β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy // Cancers (Basel). – 2021. – Vol. 13(8) – Art. no. 1830. https://doi.org/10.3390/cancers13081830
28. Li Q., Sun M., Wang M., Feng M., Yang F., Li L., Zhao J., Chang C., Dong H., Xie T., Chen J. Dysregulation of Wnt/β-catenin signaling by protein kinases in hepatocellular carcinoma and its therapeutic application // Cancer Sci. – 2021. – Vol. 112(5). – P. 1695-1706. https://doi.org/10.1111/cas.14861
29. Liu S., Tan Q., Song Y., Shi Y., Han X. Anti-p53 autoantibody in blood as a diagnostic biomarker for colorectal cancer: A meta-analysis // Scand. J. Immunol. – 2020. – Vol. 91(2). – Art. no. e12829. https://doi.org/10.1111/sji.12829
30. Beaufrère A., Paradis V. Hepatocellular adenomas: review of pathological and molecular features // Hum. Pathol. – 2021. – Vol. 112. – P. 128-137. https://doi.org/10.1016/j.humpath.2020.11.016
31. Khalaf A.M., Fuentes D., Morshid A.I., Burke M.R., Kaseb A.O., Hassan M., Hazle J.D., Elsayes K.M. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance // J. Hepatocell. Carcinoma. – 2018. – Vol. 2018(5). – P. 61-73. https://doi.org/10.2147/JHC.S156701
32. Müller M., Bird T.G., Nault J.C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma // J. Hepatol. – 2020. – Vol. 72(5). – P. 990-1002. https://doi.org/10.1016/j.jhep.2020.01.019
33. Eslam M., Valenti L., Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. // J. Hepatol. – 2018. – Vol. 68 (2). – P. 268-279. https://doi.org/10.1016/j.jhep.2017.09.003
34. Yip T.C., Lee H.W., Chan W.K., Wong G.L., Wong V.W. Asian perspective on NAFLD-associated HCC // J. Hepatol. – 2022. – Vol. 76 (3). – P. 726-734. https://doi.org/10.1016/j.jhep.2021.09.024
35. Shen J., Wong G.L., Chan H.L., Chan H.Y., Yeung D.K., Chan R.S., Chim A.M., Chan A.W., Choi P.C., Woo J., Chu W.C., Wong V.W. PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome // Aliment. Pharmacol. Ther. – 2014. – Vol. 39(5). – P. 532-539. https://doi.org/10.1111/apt.12609
36. Chan A.W., Wong G.L., Chan H.Y., Tong J.H., Yu Y.H., Choi P.C., Chan H.L., To K.F., Wong VW. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B // J. Gastroenterol. Hepatol. – 2017. – Vol. 32(3). – P. 667-676. https://doi.org/10.1111/jgh.13536
37. Bianco C., Jamialahmadi O., Pelusi S., Baselli G., Dongiovanni P., Zanoni I., Santoro L., Maier S., Liguori A., Meroni M., Borroni V., D’Ambrosio R., Spagnuolo R., Alisi A., Federico A., Bugianesi E., Petta S., Miele L., Vespasiani-Gentilucci U., Anstee Q.M., Stickel F., Hampe J., Fischer J., Berg T., Fracanzani A.L., Soardo G., Reeves H., Prati D., Romeo S., Valenti L. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores // J. Hepatol. – 2021. – Vol. 74(4). – P.775-782. https://doi.org/10.1016/j.jhep.2020.11.024
38. Wong V.W., Wong G.L., Tse C.H., Chan H.L. Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese // J. Hepatol. – 2014. – Vol.61(3). – P.708-809. https://doi.org/10.1016/j.jhep.2014.04.047
39. Thabet K., Chan H.L.Y., Petta S., Mangia A., Berg T., Boonstra A., Brouwer W.P., Abate M.L., Wong V.W., Nazmy M., Fischer J., Liddle C., George J., Eslam M. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B // Hepatology. – 2017. – Vol. 65(6). – P. 1840-1850. https://doi.org/10.1002/hep.29064
40. Hiroki M., Takahiro К., Kazuki M., Shoichiro T., Daisuke M., Yutaka S., Yasuyuki Sh., Kentaro I., Yoshihiro M. Akio S., Yoshihiro O., Yu T., Yota K., Satoshi I., Shogo K., Masashi I., Takashi T., Tomomi Hashidate-Yoshida., Hideo Sh., Masanori M., Yasuharu I., Satoshi T., Eiji M., Kazuyoshi O., Hayato H., Ryotaro S., Tomohide T., Hidetoshi E., Eiichi M., Tetsuo T. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. // Hepatology. – 2023.- Vol.77(1) – P.-77-91. https://doi.org/10.1002/hep.32573