Methylation of a group of microRNA genes: markers of renal cell carcinoma metastasis

Background. Renal cell carcinoma (RCC) is asymptomatic up to severe stages and is characterized by a high mortality rate, reaching 90 % with the development of a metastatic process.

Objective: to determine the group of microRNA genes, the methylation of which is associated with the progression of the disease, in particular, with metastasis.

Materials and methods. Methylation-specific polymerase chain reaction in a representative sample of RCC patients (98 cases) showed an increase in the methylation status of 6 microRNA genes (MIR9-1, MIR9-3, MIR34b/c, MIR130b, MIR1258, MIR107) in tumor DNA samples relative to matched samples of histologically unchanged tissue.

Results. For 4 genes (MIR9-1, MIR107, MIR130b, MIR1258), a significant association of methylation with late (III-IV) stages, tumor size, loss of differentiation, and metastasis to lymph nodes or distant organs was shown. These 4 genes were used to compose a potential metastatic prognosis marker system with a clinical sensitivity of 68 % and a specificity of 84 % (area under curve 0.83), which will be applied in the final development of a system for personalized therapy of RCC patients.

Conclusion. The association of methylation of the MIR1258 with RCC metastasis has been shown for the first time and is of independent interest as a new promising marker for the prognosis of metastatic relapses.

1. Eden A., Gaudet F., Waghmare A., Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003;300(5618):455. DOI: 10.1126/science.1083557.

2. Deaton A.M., Bird A. CpG islands and the regulation of transcription. Genes Dev 2011;25(10):1010-22. DOI: 10.1101/gad.2037511.

3. Baylin S.B., Jones P.A. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol 2016;8(9):019505. DOI: 10.1101/cshperspect.a019505.

4. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74. DOI: 10.1016/j.cell.2011.02.013.

5. Pfeifer G.P. Defining driver DNA methylation changes in human cancer. Int J Mol Sci 2018;19(4):1166. DOI: 10.3390/ijms19041166.

6. Locke W.J., Guanzon D., Ma C. et al. DNA Methylation cancer biomarkers: translation to the clinic. Front Genet 2019;10:1150. DOI: 10.3389/fgene.2019.01150.

7. Vrba L., Munoz-Rodriguez J.L., Stampfer M.R., Futscher B.W. MiRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer. PLoS One 2013;8(1):54398. DOI: 10.1371/journal.pone.0054398.

8. Kunej T., Godnic I., Ferdin J. et al. Epigenetic regulation of microRNAs in cancer: an integrated review of literature. Mut Res 2011;717(1-2):77-84. DOI: 10.1016/j.mrfmmm.2011.03.008.

9. Piletic K., Kunej T. MicroRNA epigenetic signatures in human disease. Arch Toxicol 2016;90(10):2405-19. DOI: 10.1007/s00204-016-1815-7.

10. Moutinho C., Esteller M. MicroRNAs and epigenetics. Adv Cancer Res 2017;135:189-220. DOI: 10.1016/bs.acr.2017.06.003.

11. Rykov S.V., Khodyrev D.S., Pronina I.V. et al. Novel miRNA genes methylated in lung tumors. Genetika = Genetics 2013;49(7):896-901. (In Russ.). DOI: 10.1134/S1022795413070119.

12. Loginov V.I., Burdennyy A.M., Pronina I.V. et al. Novel miRNA genes hypermethylated in breast cancer. Molekulyarnaya biologiya = Molecular Biology 2016;50(5):797-802. (In Russ.). DOI: 10.7868/S0026898416050104.

13. Pronina I.V., Loginov V.I., Burdennyy A.M. et al. DNA methylation contributes to deregulation of 12 cancerassociated microRNAs and breast cancer progression. Gene 2017;604:1-8. DOI: 10.1016/j.gene.2016.12.018.

14. Loginov V.I., Rykov S.V., Fridman M.V., Braga E.A. Methylation of miRNA genes and oncogenesis. Biohimiya = Biochemistry 2015;80(2):184-203. (In Russ.). DOI: 10.1134/S0006297915020029.

15. Beresneva E.V., Rykov S.V., Khodyrev D.S. et al. Methylation profile of group of miRNA genes in clear cell renal cell carcinoma; involvement in cancer progression. Genetika = Genetics 2013;49(3):366-75. (In Russ.). DOI: 10.1134/S1022795413030034.

16. Beresneva E.V., Loginov V.I., Khodyrev D.S. et al. The hypermethylated genes microRNA as potential markers of clear-cell carcinoma of kidney. Klinicheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics 2017;62(1):13-8. (In Russ.). DOI: 10.18821/0869-2084-2017-62-1-13-18.

17. Loginov V.I., Beresneva E.V., Kazubskaya T.P. et al. Methylation of 10 miRNA genes in clear cell renal cell carcinoma and their diagnostic value. Onkourologiya = Cancer Urology 2017;13(3):27-33. (In Russ.). DOI: 10.17650/1726-9776-2017-13-3-27-33.

18. Cairns P. Renal cell carcinoma. Cancer Biomark 2011;9(1-6):461-73. DOI: 10.3233/CBM-2011-0176.

19. Vasudev N.S., Selby P.J., Banks R.E. Renal cancer biomarkers: the promise of personalized care. BMC Med 2012;10:112. DOI: 10.1186/1741-7015-10-112.

20. Rydzanicz M., Wrzesinski T., Bluyssen H.A., Wesoly J. Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications. Cancer Lett 2013;341(2):111-26. DOI: 10.1016/j.canlet.2013.08.006.

21. Randall J.M., Millard F., Kurzrock R. Molecular aberrations, targeted therapy, and renal cell carcinoma: current state- of-the-art. Cancer Metastasis Rev 2014;33(4):1109-24. DOI: 10.1007/s10555-014-9533-1.

22. State of oncological care in Russia in 2015. Eds.: A.D. Kaprin, V.V. Starinskiy, G.V. Petrova. Moscow: MNIOI im. P.A. Gertsena filial FGBU “NMITS radiologii” Minzdrava Rossii, 2016. 236 p. (In Russ.).

23. Hwang J.S., Jeong E.J., Choi J. et al. MicroRNA-1258 inhibits the proliferation and migration of human colorectal cancer cells through suppressing CKS1B expression. Genes 2019;10(11):912. DOI: 10.3390/genes10110912.

24. Zhao X. MiR-1258 regulates cell proliferation and cell cycle to inhibit the progression of breast cancer by targeting E2F1. Biomed Res Int 2020;2020:e1480819. DOI: 10.1155/2020/1480819.

25. Wang L.Q., Kumar S., Calin G.A. et al. Frequent methylation of the tumour suppressor miR-1258 targeting PDL1: implication in multiple myeloma-specific cytotoxicity and prognostification. Br J Haematol 2020;190(2):249-61. DOI: 10.1111/bjh.16517.

26. Apanovich N.V., Peters M.V., Apanovich P.V. et al. The Genes - candidates for prognostic markers of metastasis by expression level in clear cell renal cell cancer. Diagnostics 2020;10(1):30. DOI: 10.3390/diagnostics10010030.

27. Apanovich N.V., Peters M.V., Apanovich P.V. et al. Association of target therapy gene expression with metastasizing of clear-cell renal cell carcinoma. Bull Exp Biol Med 2018;166(2):257-9. DOI: 10.1007/s10517-018-4327-z.

28. Apanovich N.V., Peters M.V., Apanovich P.V. et al. Expression profiles of genes - potential therapy targets - and their relationship to survival in renal cell carcinoma. Dokl Biochem Biophys 2018;478(1):14-7. DOI: 10.1134/S1607672918010040.

29. Apanovich N.V., Peters M.V., Korotaeva A.A. et al. Molecular genetic diagnostics of clear cell renal cell carcinoma. Cancer Urol 2016;12(4):16-20. DOI: 10.17650/1726-9776-2016-12-4-16-20.

30. Machackova T., Mlcochova H., Stanik M. et al. MiR-429 is linked to metastasis and poor prognosis in renal cell carcinoma by affecting epithelial-mesenchymal transition. Tumour Biol 2016;37(11):14653-8. DOI: 10.1007/s13277-016-5310-9.

31. Saleeb R., Kim S.S., Ding Q. et al. The miR-200 family as prognostic markers in clear cell renal cell carcinoma. Urol Oncol 2019;37(12):955-63. DOI: 10.1016/j.urolonc.2019.08.008.

32. Lokeshwar S.D., Talukder A., Yates T.J. et al. Molecular characterization of renal cell carcinoma: a potential three- microRNA prognostic signature. Cancer Epid Biomark Prev 2018;27(4):464-72. DOI: 10.1158/1055-9965.EPI-17-0700.

33. Apanovich N.V., Loginov V.I., Apanovich P.V. et al. A joint determination of gene expression and methylation for the diagnosis of clear cell renal cancer. Onkourologiya = Cancer Urology 2018;14(4): 16-21. (In Russ.). DOI: 10.17650/1726-9776-2018-14-4-16-21