New opportunities for early prediction of precancerous and cancerous lesions of the cervix: risk stratification based on the analysis of gene methylation

• Alexander O. Andreev
• Guldana R. Bayramova
• Andrew R. Zaretsky
• Denis V. Rebrikov
• Igor I. Baranov

Abstract

Nowadays, cervical cancer (CC) remains one of the urgent problems of world health. Today, close attention is paid to the organization of screening for CC and increasing the level of its predictive effectiveness. Thus, given the limited capabilities of already known screening methods, such as testing for HPV DNA and cytological examination, many researchers are studying the prospects for the development and introduction into clinical practice of new diagnostic methods that could complement or, possibly, a worthy alternative to conventional screening methods for cervical cancer. One of these methods may be the analysis of DNA methylation of certain genes, the modification of which is most characteristic of malignant neoplasms of the cervix. On the example of many studies, it was shown that the detection of abnormal methylation of various genes positively correlated not only with the risk of developing cervical cancer, but also with precancerous lesions of the cervix. This article presents the experience accumulated in the world of applying the analysis of hypermethylation of various panels of genes in relation to determining the risks of developing cervical cancer, HSIL and LSIL.

Keywords:squamous intraepithelial lesions; epigenetic changes; DNA methylation

REFERENCES

1. Kaprin A.D. Malignant neoplasms in Russia in 2020 (morbidity and mortality). In: A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU «NMITs radiologii» Minzdrava Rossii, 2021: 252 p. (in Russian)

2. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition. World Health Organization, 2021.

3. Cervical intraepithelial neoplasia, erosion and ectropion of the cervix: Clinical guidelines, Rossiyskoe obshhestvo akusherov-ginekologov, 2020. (in Russian)

4. Bayramova G.R., Prilepskaya V.N., Smol’nikova V.Yu., Yureneva S.V. HPV-associated cervicitis: diagnosis, treatment and prevention. A textbook. Moscow: ID Tret’yakov, 2022: 90 p. (in Russian)

5. Inturrisi F., Bogaards J.A., Heideman D.A.M., Meijer C.J.L.M., Berkhof J. Risk of cervical intraepithelial neoplasia grade 3 or worse in HPV-positive women with normal cytology and five-year type concordance: a randomized comparison. Cancer Epidemiol Biomarkers Prev. 2021; 30 (3): 485–91. DOI: https://doi.org/10.1158/1055-9965

6. Bonde J., Floore A., Ejegod D., Vink F.J., Hesselink A., van de Ven P.M., et al. Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: a large European multicenter study. Int J Cancer. 2021; 148 (2): 396–405. DOI: https://doi.org/10.1002/ijc.33320 Epub 2020 Oct 21. PMID: 32997803; PMCID: PMC7756277.

7. Hampl M., Hesselink A.T., Meijer C.J.L.M., Denecke A., Einhorn I., Reinecke-Luethge A., et al.; Members of the German Study Group of Colposcopy (SGK). Evaluation of FAM19A4/miR124-2 methylation performance in the management of CIN3 diagnosed pregnant women. Int J Cancer. 2022; 151 (9): 1578–85. DOI: https://doi.org/10.1002/ijc.34153 Epub 2022 Jun 20. PMID: 35666529.

8. Hillyar C.R., Kanabar S.S., Pufal K.R., Lawson A.W., Saw Hee J.L., Rallis K.S., et al. A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer. Epigenomics. 2022; 14 (18): 1055–72. DOI: https://doi.org/10.2217/epi-2022-0160 Epub 2022 Sep 28. PMID: 36169190.

9. Zhang L., Tan W., Yang H., Zhang S., Dai Y. Detection of host cell Gene/HPV DNA methylation markers: a promising triage approach for cervical cancer. Front Oncol. 2022; 12: 831949. DOI: https://doi.org/10.3389/fonc.2022.831949 PMID: 35402283; PMCID: PMC8990922.

10. Kremer W.W., Steenbergen R., Heideman D., Kenter G.G., Meijer C. The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review. BJOG. 2021; 128 (3): 504–14. DOI: https://doi.org/10.1111/1471-0528.16395 Epub 2020 Aug 9. PMID: 32619334; PMCID: PMC7818489.

11. Jones P.A., Baylin S.B. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3 (6): 415–28. DOI: https://doi.org/10.1038/nrg816 PMID: 12042769.

12. Herman J.G., et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998; 95: 6870–5.

13. El Aliani A., El-Abid H., El Mallali Y., Attaleb M., Ennaji M.M., El Mzibri M. Association between gene promoter methylation and cervical cancer development: global distribution and a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2021; 30 (3): 450–9. DOI: https://doi.org/10.1158/1055-9965.epi-20-0833 Epub 2021 Jan 13. PMID: 33441308.

14. Pfeifer G.P., Tang M., Denissenko M.F. Mutation hotspots and DNA methylation. Curr Top Microbiol Immunol. 2000; 249: 1–19.

15. Yoon J.H., et al. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res. 2001; 61: 7110–7.

16. Kong L., Wang L., Wang Z., Xiao X., You Y., Wu H., et al. DNA methylation for cervical cancer screening: a training set in China. Clin Epigenetics. 2020; 12 (1): 91. DOI: https://doi.org/10.1186/s13148-020-00885-7 PMID: 32576279; PMCID: PMC7310541.

17. Vink F.J., Meijer C.J.L.M., Clifford G.M., Poljak M., Oštrbenk A., Petry K.U., et al. FAM19A4/miR124-2 methylation in invasive cervical cancer: a retrospective cross-sectional worldwide study. Int J Cancer. 2020; 147 (4): 1215–21. DOI: https://doi.org/10.1002/ijc.32614 Epub 2019 Sep 9. PMID: 31390052; PMCID: PMC7383900.

18. De Strooper L.M.A., Berkhof J., Steenbergen R.D.M., Lissenberg-Witte B.I., Snijders P.J.F., Meijer C., et al. Cervical cancer risk in HPV-positive women after a negative FAM19A4/mir124-2 methylation test: a post hoc analysis in the POBASCAM trial with 14 year follow-up. Int J Cancer. 2018; 143: 1541–8.

19. Bu Q., Wang S., Ma J., Zhou X., Hu G., Deng H., et al. The clinical significance of FAM19A4 methylation in high-risk HPV-positive cervical samples for the detection of cervical (pre)cancer in Chinese women. BMC Cancer. 2018; 18 (1): 1182. DOI: https://doi.org/10.1186/s12885-018-4877-5 PMID: 30486875; PMCID: PMC6263049.

20. Wang S.F., Bu Q.W., Zhang L., Ma J.W., Heng Y., Luo J.Q., et al. [Detection and analysis of FAM19A4 promoter methylation in cervical exfoliated cells]. Zhonghua Yi Xue Za Zhi. 2019; 99 (25): 1963–7. DOI: https://doi.org/10.3760/cma.j.issn.0376-2491.2019.25.012 PMID: 31269601. (in Chinese)

21. Wang F., Liu M., Li X., Tang H. MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells. FEBS Lett. 2013; 587 (5): 488–95. DOI: https://doi.org/10.1016/j.febslet.2013.01.016 Epub 2013 Jan 18. PMID: 23337879.

22. Henken F.E., Wilting S.M., Overmeer R.M., van Rietschoten J.G., Nygren A.O., Errami A., et al. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis. Br J Cancer. 2007; 97: 1457–64. DOI: https://doi.org/10.1038/sj.bjc.6604055

23. Widschwendter A., Muller H.M., Fiegl H., Ivarsson L., Wiedemair A., Muller-Holzner E., et al. DNA methylation in serum and tumors of cervical cancer patients. Clin Cancer Res. 2004; 10: 565–71. DOI: https://doi.org/10.1158/1078-0432.CCR-0825-03

24. Overmeer R.M., Henken F.E., Bierkens M., Wilting S.M., Timmerman I., Meijer C.J., et al. Repression of MAL tumor suppressor activity by promoter methylation during cervical carcinogenesis. J Pathol. 2009; 219 (3): 327–36.

25. Lujambio A., Ropero S., Ballestar E., Fraga M.F., Cerrato C., Setien F., et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007; 67: 1424–9. DOI: https://doi.org/10.1158/0008-5472.CAN-06-4218

26. Wilting S.M., van Boerdonk R.A., Henken F.E., Meijer C.J., Diosdado B., Meijer G.A., et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010; 9: 167. DOI: https://doi.org/10.1186/1476-4598-9-167 PMID: 20579385; PMCID: PMC2917428.

27. Shen S., Zhang S., Liu P., Wang J., Du H. Potential role of microRNAs in the treatment and diagnosis of cervical cancer. Cancer Genet. 2020; 248–249: 25–30. DOI: https://doi.org/10.1016/j.cancergen.2020.09.003

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