DNA hypermethylation of tumor suppressor genes TWIST1, GATA4, MUS81 and NTRK1 in endometrial hyperplasia

Česká verze

Authors: Ondřej Dvořák ¹ ; Marcela Slavíčková ² ; Jan Laco ³ ; Martin Štěpán ¹ ; Eva Čermáková ⁴ ; Jiří Špaček ¹
Authors place of work: Porodnická a gynekologická klinika LF UK a FN Hradec Králové ¹; Ústav klinické bio chemie a dia gnostiky, LF UK a FN Hradec Králové ²; Fingerlandův ústav patologie, LF UK a FN Hradec Králové ³; Ústav lékařské bio fyziky, LF Hradec Králové ⁴
Published in the journal: Ceska Gynekol 2024; 89(4): 261-268
Category: Původní práce
doi: https://doi.org/10.48095/cccg2024261

Summary

Objective: To investigate DNA methylation of specific tumor suppressor genes in endometrial hyperplasia compared to normal endometrial tissue. File and methodology: To search for epigenetic events, methylation-specific multiplex ligation-dependent probe amplification was employed to compare the methylation status of 40 tissue samples with atypical endometrial hyperplasia, 40 tissue samples with endometrial hyperplasia without atypia, and 40 control tissue samples with a normal endometrium. Results and conclusion: Differences in DNA methylation among the groups were found in TWIST1, GATA4, MUS81, and NTRK1 genes (TWIST1: atypical hyperplasia 67.5%, benign hyperplasia 2.5%, normal endometrium 22.5%; P < 0.00001; GATA4: atypical hyperplasia 95%, benign hyperplasia 65%, normal endometrium 22.5%; P < 0.00001; MUS81: atypical hyperplasia 57.5%, benign hyperplasia 22.5%, normal endometrium 5%; P < 0.00001; NTRK1: atypical hyperplasia 65%, benign hyperplasia 27.5%, normal endometrium 10%; P < 0.00001). Higher methylation rates were observed for the tumor suppressor genes of TWIST1, GATA4, MUS81, and NTRK1 in samples with atypical endometrial hyperplasia compared to samples with normal endometrial tissue, and higher methylation rates were found in samples with atypical endometrial hyperplasia compared to samples of benign endometrial hyperplasia. DNA methylation of TWIST1, GATA4, MUS81, and NTRK1 is involved in the pathogenesis of atypical endometrial hyperplasia.

Keywords:

Epigenetics – Methylation – endometrial hyperplasia – NTRK1 – TWIST1 – GATA4 – MUS81

Zdroje

1. Singh G, Puckett Y. Endometrial Hyperplasia. Treasure Island (FL): StatPearls Publishing 2024.

2. Hsu YT, Gu F, Huang YW et al. Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer. Clin Cancer Res 2013; 19 (22): 6272–6285. doi: 10.1158/1078-0432.CCR-13-1734.

3. Chandra V, Kim JJ, Benbrook DM et al. Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol 2016; 27 (1): e8. doi: 10.3802/jgo.2016.27.e8.

4. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985; 56 (2): 403–412. doi: 10.1002/1097-0142 (19850715) 56: 2<403:: aid-cncr2820560233>3.0.co; 2-x.

5. Montgomery BE, Daum GS, Dunton CJ. Endometrial hyperplasia: a review. Obstet Gynecol Surv 2004; 59 (5): 368–378. doi: 10.1097/0000 6254-200405000-00025.

6. Lacey JV Jr, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas 2009; 63 (1): 39–44. doi: 10.1016/j.maturitas.2009.02.005.

7. Lacey JV Jr, Chia VM, Rush BB et al. Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan. Int J Cancer 2012; 131 (8): 1921–1929. doi: 10.1002/ijc.27457.

8. Nieminen TT, Gylling A, Abdel-Rahman WM et al. Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia. Clin Cancer Res 2009; 15 (18): 5772–5783. doi: 10.1158/1078-0432.CCR-09-0506.

9. Dvorak O, Ndukwe M, Slavickova M et al. DNA methylation of selected tumor suppressor genes in endometrial hyperplasia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2024; 168 (1): 68–73. doi: 10.5507/bp.2022.053.

10. Pavicic W, Perkiö E, Kaur S et al. Altered methylation at microRNA-associated CpG islands in hereditary and sporadic carcinomas: a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) -based approach. Mol Med 2011; 17 (7–8): 726–735. doi: 10.2119/molmed.2010.00239.

11. Trimarchi MP, Yan P, Groden J et al. Identification of endometrial cancer methylation features using combined methylation analysis methods. PLoS One 2017; 12 (3): e0173242. doi: 10.1371/journal.pone.0173242.

12. Khan MA, Chen HC, Zhang D et al. Twist: a molecular target in cancer therapeutics. Tumour Biol 2013; 34 (5): 2497–2506. doi: 10.1007/s13277-013-1002-x.

13. Martin TA, Goyal A, Watkins G et al. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 2005; 12 (6): 488–496. doi: 10.1245/ASO.2005.04.010.

14. van Doorn R, Dijkman R, Vermeer MH et al. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis. Cancer Res 2004; 64 (16): 5578–5586. doi: 10.1158/0008-5472.CAN-04-1253.

15. Roberts CM, Tran MA, Pitruzzello MC et al. TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling. Sci Rep 2016; 6: 37652. doi: 10.1038/srep37652.

16. Juanqing L, Hailan Y, Xiangwei F et al. Relationship between the methylation levels of Twist gene and pathogenesis of endometriosis. Cell Mol Biol (Noisy-le-grand) 2019; 65 (3): 94–100.

17. Shen J, Chen Q, Li N et al. TWIST1 expression and clinical significance in type I endometrial cancer and premalignant lesions: a retrospective clinical study. Medicine (Baltimore) 2020; 99 (48): e23397. doi: 10.1097/MD.0000000000023397.

18. Wang XJ, Chen XH. Expression and significance of TWIST1 and MMP-2 in endometrial endometrioid adenocarcinoma. Zhonghua Zhong Liu Za Zhi 2012; 34 (8): 588–591. doi: 10.3760/cma.j.issn.0253-3766.2012.08.006.

19. Yusup A, Huji B, Fang C et al. Expression of trefoil factors and TWIST1 in colorectal cancer and their correlation with metastatic potential and prognosis. World J Gastroenterol 2017; 23 (1): 110–120. doi: 10.3748/wjg.v23.i1.110.

20. Perrino C, Rockman HA. GATA4 and the two sides of gene expression reprogramming. Circ Res 2006; 98 (6): 715–716. doi: 10.1161/01.RES.0000217593.07196.af.

21. Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 2000; 275 (50): 38949–38952. doi: 10.1074/jbc.R000029200.

22. Akiyama Y, Watkins N, Suzuki H et al. GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol Cell Biol 2003; 23 (23): 8429–8439. doi: 10.1128/MCB.23.23.84 29-8439.2003.

23. Guo M, Akiyama Y, House MG et al. Hypermethylation of the GATA genes in lung cancer. Clin Cancer Res 2004; 10 (23): 7917–7924. doi: 10.1158/1078-0432.CCR-04-1140.

24. Guo M, House MG, Akiyama Y et al. Hypermethylation of the GATA gene family in esophageal cancer. Int J Cancer 2006; 119 (9): 2078–2083. doi: 10.1002/ijc.22092.

25. Wen XZ, Akiyama Y, Pan KF et al. Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas. World J Gastroenterol 2010; 16 (10): 1201–1208. doi: 10.3748/wjg.v16.i10.1201.

26. Chmelarova M, Kos S, Dvorakova E et al. Importance of promoter methylation of GATA4 and TP53 genes in endometrioid carcinoma of endometrium. Clin Chem Lab Med 2014; 52 (8): 1229–1234. doi: 10.1515/cclm-2013-0162.

27. Lukaszewicz A, Howard-Till RA, Loidl J. MUS81 nuclease and Sgs1 helicase are essential for meiotic recombination in a protist lacking a synaptonemal complex. Nucleic Acids Res 2013; 41 (20): 9296–9309. doi: 10.1093/nar/gkt703.

28. Chen S, Geng X, Syeda MZ et al. Human MUS81: a fence-sitter in cancer. Front Cell Dev Biol 2021; 9: 657305. doi: 10.3389/fcell.2021. 657305.

29. Gong L, Tang Y, Jiang L et al. Expression of MUS81 mediates the sensitivity of castration-resistant prostate cancer to olaparib. J Immunol Res 2022; 2022: 4065580. doi: 10.1155/2022/ 4065580.

30. Lu R, Xie S, Wang Y et al. MUS81 participates in the progression of serous ovarian cancer associated with dysfunctional DNA repair system. Front Oncol 2019; 9: 1189. doi: 10.3389/fonc.2019.01189.

31. Wang T, Zhang P, Li C et al. MUS81 inhibition enhances the anticancer efficacy of talazoparib by impairing ATR/CHK1 signaling pathway in gastric cancer. Front Oncol 2022; 12: 844135. doi: 10.3389/fonc.2022.844 135.

32. Wu F, Su SC, Tan GQ et al. MUS81 knockdown sensitizes colon cancer cells to chemotherapeutic drugs by activating CHK1 pathway. Clin Res Hepatol Gastroenterol 2017; 41 (5): 592–601. doi: 10.1016/j.clinre.2017.01.011.

33. Xie S, Zheng H, Wen X et al. MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer. Biochem Biophys Res Commun 2016; 476 (4): 493–500. doi: 10.1016/j.bbrc.2016.05.152.

34. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319 (6056): 743–748. doi: 10.1038/319743a0.

35. O‘haire S, Franchini F, Kang YJ et al. Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Sci Rep 2023; 13 (1): 4116. doi: 10.1038/s41598-023-31055-3.

36. Croce S, Hostein I, McCluggage WG. NTRK and other recently described kinase fusion positive uterine sarcomas: a review of a group of rare neoplasms. Genes Chromosomes Cancer 2021; 60 (3): 147–159. doi: 10.1002/gcc.22910.

37. Mohammad N, Stewart CJ, Chiang S et al. p53 immunohistochemical analysis of fusion-positive uterine sarcomas. Histopathology 2021; 78 (6): 805–813. doi: 10.1111/his.14292.

38. Grant L, Boyle W, Williams S et al. Uterine neurotrophic tyrosine receptor kinase rearranged spindle cell neoplasms: three cases of an emerging entity. Int J Gynecol Pathol 2023; 43 (4): 326–334. doi: 10.1097/PGP.00000000000 00988.

39. Saeki H, Horimoto Y, Hlaing MT et al. Clinicopathological and molecular pathological characteristics in tamoxifen-related endometrial cancer. Oncol Lett 2024; 27 (1): 9. doi: 10.3892/ol.2023.14142.

40. Heichman KA, Warren JD. DNA methylation biomarkers and their utility for solid cancer diagnostics. Clin Chem Lab Med 2012; 50 (10): 1707–1721. doi: 10.1515/cclm-2011-0935.

ORCID autorů

O. Dvořák 0000-0003-1372-3729

M. Štěpán 0000-0002-5976-2291

J. Laco 0000-0002-9602-7501

M. Slavíčková 0000-0002-7891-9979

E. Čermáková 0000-0003-3413-4149

Doručeno/Submitted: 21. 4. 2024

Přijato/Accepted: 23. 5. 2024

MUDr. Ondřej Dvořák

Porodnická a gynekologická klinika

LF UK a FN Hradec Králové

Sokolská 581