Associations of MGMT promoter hypermethylation with squamous intraepithelial lesion and cervical carcinoma: A meta-analysis

Autoři: Jin Huang aff001;  Jia-You Luo aff002;  Hong-Zhuan Tan aff001
Působiště autorů: Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan, China aff001;  Department of Women and Children Health, School of Public Health, Central South University, Changsha, Hunan, China aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article



In this research, an meta-analysis was performed for assessment of the associations between O6-methyguanine-DNA methyltransferase (MGMT) promoter hypermethylation possessing low-grade intraepithelial lesion (LSIL), high-grade intraepithelial lesion (HSIL), cervical cancer (CC), and clinicopathological characters of CC.


Literature selection were conducted through searching PubMed, Web of science, EMBASE, China National Knowledge Infrastructure and Wanfang databases (up to November 2018). An assessment of associations between MGMT methylation and LSIL, HSIL, CC risk and clinicopathological characteristics was performed through pooled odds ratios (ORs) with relevant 95% confidence intervals (CIs). Subgroup analyses, meta-regressions and Galbraith plots were conducted to conduct an exploration on the possible sources of heterogeneity. The genome-wide DNA methylation array studies were extracted from Gene Expression Omnibus (GEO) databases for validation of these outcomes.


In this meta-analysis of 25 published articles, MGMT hypermethylation gradually elevated the rates among control group (12.16%), LSIL (20.92%), HSIL (36.33%) and CC (41.50%) specimens. MGMT promoter methylation was significant associated with the increased risk of LSIL by 1.74-fold (P<0.001), HSIL by 3.71-fold (P<0.001) and CC by 7.08-fold (P<0.001) compared with control. A significant association between MGMT promoter methylation with FIGO stage was also found (OR = 2.81, 95% CI: 1.79–4.41, p<0.001). The results of GEO datasets showed that 5 CpG sites in MGMT with a great diagnostic value for the screening of cervical cancer.


The meta-analysis indicated the association between MGMT promoter hypermethylation and squamous intraepithelial lesion and cervical cancer. MGMT methylation detection might have a potential value to be an epigenetic marker for the clinical diagnosis of cervical cancer.

Klíčová slova:

Carcinomas – Cervical cancer – DNA methylation – Histology – China – Lesions – Methylation


1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: a cancer journal for clinicians. 2015;65(2):87–108. Epub 2015/02/06. doi: 10.3322/caac.21262 25651787.

2. Di J, Rutherford S, Chu C. Review of the Cervical Cancer Burden and Population-Based Cervical Cancer Screening in China. Asian Pacific journal of cancer prevention: APJCP. 2015;16(17):7401–7. Epub 2015/12/03. doi: 10.7314/apjcp.2015.16.17.7401 26625735.

3. Chen JY, Wang ZL, Wang ZY, Yang XS. The risk factors of residual lesions and recurrence of the high-grade cervical intraepithelial lesions (HSIL) patients with positive-margin after conization. Medicine. 2018;97(41):e12792. Epub 2018/10/14. doi: 10.1097/MD.0000000000012792 30313104; PubMed Central PMCID: PMC6203583.

4. Vale DB, Westin MC, Zeferino LC. High-grade squamous intraepithelial lesion in women aged <30 years has a prevalence pattern resembling low-grade squamous intraepithelial lesion. Cancer cytopathology. 2013;121(10):576–81. Epub 2013/06/15. doi: 10.1002/cncy.21312 23765869.

5. Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. International journal of cancer. 2012;131(10):2349–59. Epub 2012/02/11. doi: 10.1002/ijc.27485 22323075.

6. Robertson KD. DNA methylation and human disease. Nature reviews Genetics. 2005;6(8):597–610. Epub 2005/09/02. doi: 10.1038/nrg1655 16136652.

7. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer research. 1999;59(4):793–7. Epub 1999/02/24. 10029064.

8. Rehman AU, Saikia S, Iqbal MA, Ahmad I, Sadaf, Anees A, et al. Decreased expression of MGMT in correlation with aberrant DNA methylation in esophageal cancer patients from North India. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2017;39(6):1010428317705770. Epub 2017/06/18. doi: 10.1177/1010428317705770 28621225.

9. Zhang Y, Tong T. Clinical Significance of O-6-Methylguanine-DNA-Methyltransferase Promoter Methylation in Patients with Esophageal Carcinoma: A Systematic Meta-Analysis. Digestive diseases (Basel, Switzerland). 2018;36(2):89–97. Epub 2017/12/20. doi: 10.1159/000481342 29258097.

10. Chen C, Hua H, Han C, Cheng Y, Cheng Y, Wang Z, et al. Prognosis value of MGMT promoter methylation for patients with lung cancer: a meta-analysis. International journal of clinical and experimental pathology. 2015;8(9):11560–4. Epub 2015/12/01. 26617891; PubMed Central PMCID: PMC4637707.

11. Wang BH, Li YY, Han JZ, Zhou LY, Lv YQ, Zhang HL, et al. Gene methylation as a powerful biomarker for detection and screening of non-small cell lung cancer in blood. Oncotarget. 2017;8(19):31692–704. Epub 2017/04/14. doi: 10.18632/oncotarget.15919 28404957; PubMed Central PMCID: PMC5458240.

12. Yang Z, Li F. O-6-methylguanine-DNA methyltransferase gene promoter methylation and lung cancer risk: A meta-analysis. Journal of cancer research and therapeutics. 2016;12(Supplement):C233–c6. Epub 2017/02/24. doi: 10.4103/0973-1482.200745 28230024.

13. Switzeny OJ, Christmann M, Renovanz M, Giese A, Sommer C, Kaina B. MGMT promoter methylation determined by HRM in comparison to MSP and pyrosequencing for predicting high-grade glioma response. Clinical epigenetics. 2016;8:49. Epub 2016/05/10. doi: 10.1186/s13148-016-0204-7 27158275; PubMed Central PMCID: PMC4858829.

14. Banan R, Christians A, Bartels S, Lehmann U, Hartmann C. Absence of MGMT promoter methylation in diffuse midline glioma, H3 K27M-mutant. Acta neuropathologica communications. 2017;5(1):98. Epub 2017/12/17. doi: 10.1186/s40478-017-0500-2 29246238; PubMed Central PMCID: PMC5732448.

15. Alizadeh Naini M, Kavousipour S, Hasanzarini M, Nasrollah A, Monabati A, Mokarram P. O6-Methyguanine-DNA Methyl Transferase (MGMT) Promoter Methylation in Serum DNA of Iranian Patients with Colorectal Cancer. Asian Pacific journal of cancer prevention: APJCP. 2018;19(5):1223–7. Epub 2018/05/29. doi: 10.22034/APJCP.2018.19.5.1223 29801405; PubMed Central PMCID: PMC6031839.

16. Bagci B, Sari M, Karadayi K, Turan M, Ozdemir O, Bagci G. KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients. Cancer biomarkers: section A of Disease markers. 2016;17(2):133–43. Epub 2016/08/20. doi: 10.3233/cbm-160624 27540971.

17. Coppede F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World journal of gastroenterology. 2014;20(4):943–56. Epub 2014/02/28. doi: 10.3748/wjg.v20.i4.943 24574767; PubMed Central PMCID: PMC3921546.

18. Michailidi C, Theocharis S, Tsourouflis G, Pletsa V, Kouraklis G, Patsouris E, et al. Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma. Experimental biology and medicine (Maywood, NJ). 2015;240(12):1599–605. Epub 2015/04/25. doi: 10.1177/1535370215583800 25908636; PubMed Central PMCID: PMC4935349.

19. Ding Y, Yang Q, Wang B, Ye G, Tong X. The Correlation of MGMT Promoter Methylation and Clinicopathological Features in Gastric Cancer: A Systematic Review and Meta-Analysis. PloS one. 2016;11(11):e0165509. Epub 2016/11/09. doi: 10.1371/journal.pone.0165509 27824946; PubMed Central PMCID: PMC5100908.

20. Cai F, Xiao X, Niu X, Shi H, Zhong Y. Aberrant Methylation of MGMT Promoter in HNSCC: A Meta-Analysis. PloS one. 2016;11(9):e0163534. Epub 2016/09/23. doi: 10.1371/journal.pone.0163534 27657735; PubMed Central PMCID: PMC5033341.

21. Koutsimpelas D, Pongsapich W, Heinrich U, Mann S, Mann WJ, Brieger J. Promoter methylation of MGMT, MLH1 and RASSF1A tumor suppressor genes in head and neck squamous cell carcinoma: pharmacological genome demethylation reduces proliferation of head and neck squamous carcinoma cells. Oncol Rep. 2012;27(4):1135–41. Epub 2012/01/17. doi: 10.3892/or.2012.1624 22246327; PubMed Central PMCID: PMC3583513.

22. Qiao B, Zhang Z, Li Y. Association of MGMT promoter methylation with tumorigenesis features in patients with ovarian cancer: A systematic meta-analysis. Molecular genetics & genomic medicine. 2018;6(1):69–76. Epub 2017/12/02. doi: 10.1002/mgg3.349 29195029; PubMed Central PMCID: PMC5823672.

23. An N, Shi Y, Ye P, Pan Z, Long X. Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2017;42(6):2430–40. Epub 2017/08/30. doi: 10.1159/000480196 28848211.

24. Virmani AK, Muller C, Rathi A, Zoechbauer-Mueller S, Mathis M, Gazdar AF. Aberrant methylation during cervical carcinogenesis. Clinical Cancer Research. 2001;7(3):584–9. WOS:000167883100021. 11297252

25. Chen R, Zheng Y, Zhuo L, Wang S. Association between MGMT Promoter Methylation and Risk of Breast and Gynecologic Cancers: A Systematic Review and Meta-Analysis. Scientific Reports. 2017;7. doi: 10.1038/s41598-017-13208-3 WOS:000412492400009. 28986566

26. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS medicine. 2012;9(5):e1001216. Epub 2012/06/08. doi: 10.1371/journal.pmed.1001216 22675273; PubMed Central PMCID: PMC3362085.

27. Moore HM, Kelly AB, Jewell SD, McShane LM, Clark DP, Greenspan R, et al. Biospecimen reporting for improved study quality (BRISQ). Cancer cytopathology. 2011;119(2):92–101. Epub 2011/03/25. doi: 10.1002/cncy.20147 21433001.

28. Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. American journal of epidemiology. 2005;162(3):201–11. Epub 2005/07/01. doi: 10.1093/aje/kwi184 15987731.

29. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557–60. Epub 2003/09/06. doi: 10.1136/bmj.327.7414.557 12958120; PubMed Central PMCID: PMC192859.

30. Lu XC, Yu W, Tao Y, Zhao PL, Li K, Tang LJ, et al. Contribution of transforming growth factor alpha polymorphisms to nonsyndromic orofacial clefts: a HuGE review and meta-analysis. American journal of epidemiology. 2014;179(3):267–81. Epub 2013/11/19. doi: 10.1093/aje/kwt262 24243742.

31. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629–34. Epub 1997/10/06. doi: 10.1136/bmj.315.7109.629 9310563; PubMed Central PMCID: PMC2127453.

32. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. Jama. 2002;287(16):2114–9. Epub 2002/04/23. doi: 10.1001/jama.287.16.2114 11966386.

33. Flatley JE, McNeir K, Balasubramani L, Tidy J, Stuart EL, Young TA, et al. Folate Status and Aberrant DNA Methylation Are Associated With HPV Infection and Cervical Pathogenesis. Cancer Epidemiology Biomarkers & Prevention. 2009;18(10):2782–9. doi: 10.1158/1055-9965.EPI-09-0493 WOS:000270702100029. 19755648

34. da Costa Lodi CT, Michelin MA, Miranda Lima MI, Candido Murta EF, Braga LdC, Montes L, et al. Predicting cervical intraepithelial neoplasia recurrence in HIV-infected and -noninfected women by detecting aberrant promoter methylation in the CDH1, TIMP3, and MGMT genes. Archives of Gynecology and Obstetrics. 2018;298(5):971–9. doi: 10.1007/s00404-018-4899-x WOS:000446970300018. 30218185

35. Wang, L. Interaction between polycyclic aromatic hydrocarbons exposure and CpG islands methylation of RAR-β and MGMT genes in cervical intraepithelial neoplasia. Thesis. Shanxi Medical University, (2018)

36. Nan, J. Effect of HPV, folate and related suppressor gene CpG island methylation in cervical intraepithelial neoplasias and related interaction. Thesis. Shanxi Medical University, (2016).

37. Banzai C, Nishino K, Quan J, Yoshihara K, Sekine M, Yahata T, et al. Promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A genes in cervical carcinoma. International Journal of Clinical Oncology. 2014;19(1):127–32. doi: 10.1007/s10147-013-0530-0 WOS:000331700200020. 23494221

38. Lu H. et al. Relationship between methylation of MGMT gene promoter and cervical carcinoma. Zhejiang Medical Journal. 2014; 36: 1841–3.

39. Sun L-l, Cao D-y, Yang J-x, Li H, Zhou X-r, Song Z-q, et al. Population-based case-control study on DAPK1, RAR-beta 2 and MGMT methylation in liquid-based cytology. Archives of Gynecology and Obstetrics. 2012;285(5):1433–9. doi: 10.1007/s00404-011-2149-6 WOS:000302814200035. 22116316

40. Sun LL, Liu Y, Sun X, Pan L, Wu D, Wang YD. Limited Role of Promoter Methylation of MGMT and C13ORF18 in Triage of Low-Grade Squamous Intraepithelial Lesion. Chin Med J (Engl). 2018;131(8):939–44. Epub 2018/04/18. doi: 10.4103/0366-6999.229896 29664054; PubMed Central PMCID: PMC5912060.

41. Jian Y. et al. Relationship between hypermethylation of DNA repair gene MGMT and cervical carcinoma. Journal of Qinghai Medical College. 2012; 33: 90–4.

42. Spathis A, Aga E, Alepaki M, Chranioti A, Meristoudis C, Panayiotides I, et al. Promoter methylation of p16(INK4A), hMLH1, and MGMT in liquid-based cervical cytology samples compared with clinicopathological findings and HPV presence. Infectious diseases in obstetrics and gynecology. 2011;2011:927861–. doi: 10.1155/2011/927861 MEDLINE:21747645. 21747645

43. Liu, Y. MGMT promoter methylation status in serum of patients with squamous carcinoma of the cervix and the relation with hr-HPV infection. Thesis. Wenzhou Medical University. (2011).

44. Kim J-H, Choi YD, Lee JS, Lee JH, Nam JH, Choi C. Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens. Gynecologic Oncology. 2010;116(1):99–104. doi: 10.1016/j.ygyno.2009.09.032 WOS:000273108700019. 19836067

45. Iliopoulos D, Oikonomou P, Messinis I, Tsezou A. Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression. Oncology Reports. 2009;22(1):199–204. doi: 10.3892/or_00000425 WOS:000267259100028. 19513524

46. Park N-H, 이승호. Promoter hypermethylation of MGMT (O6-methylguanine-DNA methyltransferase)in cervical squamous cell carcinoma promoter과메칠화에 대한 연구. Obstetrics & Gynecology Science. 2008;51(1):24–30. KJD:ART001213600.

47. Chen, S. (2008). Detection of aberrant methylation of the promoter of MGMT gene in the tissue and plasma in Uigur cervical cancer and its clinical significance. Thesis. Shihezi University.

48. Henken FE, Wilting SM, Overmeer RM, van Rietschoten JGI, Nygren AOH, Errami A, et al. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis. British Journal of Cancer. 2007;97(10):1457–64. doi: 10.1038/sj.bjc.6604055 WOS:000250956100019. 17971771

49. Jo H, Kang S, Kim JW, Kang GH, Park NH, Song YS, et al. Hypermethylation of the COX-2 gene is a potential prognostic marker for cervical cancer. Journal of Obstetrics and Gynaecology Research. 2007;33(3):236–41. doi: 10.1111/j.1447-0756.2007.00517.x WOS:000247321600001. 17578348

50. Gao Y. et al. Promoter hypermethylation of DNA repair gene O6-Methylguanine DNA methylatransferase in cervical carcinoma. Prog Obset Gynecol. 2007: 569–72.

51. Yang H-J, Liu VWS, Wang Y, Tsang PCK, Ngan HYS. Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. Bmc Cancer. 2006;6. doi: 10.1186/1471-2407-6-212 WOS:000240420200001. 16928264

52. Lin Z, Gao M, Zhang X, Kim YS, Lee ES, Kim HK, et al. The hypermethylation and protein expression of p16 INK4A and DNA repair gene O6-methylguanine-DNA methyltransferase in various uterine cervical lesions. J Cancer Res Clin Oncol. 2005;131(6):364–70. Epub 2005/03/24. doi: 10.1007/s00432-004-0657-5 15785933.

53. Reesink-Peters N, Wisman GBA, Jeronimo C, Tokumaru CY, Cohen Y, Dong SM, et al. Detecting cervical cancer by quantitative promoter hypermethylation assay on cervical scrapings: A feasibility study. Molecular Cancer Research. 2004;2(5):289–95. WOS:000221944600003. 15192122

54. Yang HJ, Liu VWS, Wang Y, Chan KYK, Tsang PCK, Khoo US, et al. Detection of hypermethylated genes in tumor and plasma of cervical cancer patients. Gynecologic Oncology. 2004;93(2):435–40. doi: 10.1016/j.ygyno.2004.01.039 WOS:000221120500026. 15099958

55. Dong SM, Kim HS, Rha SH, Sidransky D. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clinical Cancer Research. 2001;7(7):1982–6. WOS:000169782400024. 11448914

56. Sun Y, Li S, Shen K, Ye S, Cao D, Yang J. DAPK1, MGMT and RARB promoter methylation as biomarkers for high-grade cervical lesions. International Journal of Clinical and Experimental Pathology. 2015;8(11):14939–45. WOS:000368140100133. 26823825

57. Sun W, Zaboli D, Liu Y, Arnaoutakis D, Khan T, Wang H, et al. Comparison of promoter hypermethylation pattern in salivary rinses collected with and without an exfoliating brush from patients with HNSCC. PloS one. 2012;7(3):e33642. Epub 2012/03/23. doi: 10.1371/journal.pone.0033642 22438973; PubMed Central PMCID: PMC3306276.

58. Ouadid-Ahidouch H, Rodat-Despoix L, Matifat F, Morin G, Ahidouch A. DNA methylation of channel-related genes in cancers. Biochimica et biophysica acta. 2015;1848(10 Pt B):2621–8. Epub 2015/02/24. doi: 10.1016/j.bbamem.2015.02.015 25703813.

59. Huang T, Chen X, Hong Q, Deng Z, Ma H, Xin Y, et al. Meta-analyses of gene methylation and smoking behavior in non-small cell lung cancer patients. Sci Rep. 2015;5:8897. Epub 2015/03/11. doi: 10.1038/srep08897 25754026; PubMed Central PMCID: PMC4354004.

60. Hengstler JG, Tanner B, Moller L, Meinert R, Kaina B. Activity of O(6)-methylguanine-DNA methyltransferase in relation to p53 status and therapeutic response in ovarian cancer. Int J Cancer. 1999;84(4):388–95. Epub 1999/07/15. doi: 10.1002/(sici)1097-0215(19990820)84:4<388::aid-ijc10>;2-3 10404091.

61. Fu T, Sharmab A, Xie F, Liu Y, Li K, Wan W, et al. Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma. PloS one. 2016;11(9):e0162929. Epub 2016/09/20. doi: 10.1371/journal.pone.0162929 27643594; PubMed Central PMCID: PMC5028050 for MDx Health Inc. and BioNumerik Pharmaceuticals Inc. Nita Ahuja has grant funding from Astex and has licensed biomarkers to Cepheid Inc. She has served as consultant for Ethicon. No potential conflicts of interest were disclosed by the other authors.

62. Nilsson TK, Lof-Ohlin ZM, Sun XF. DNA methylation of the p14ARF, RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients. Int J Oncol. 2013;42(1):127–33. Epub 2012/11/07. doi: 10.3892/ijo.2012.1682 23128528; PubMed Central PMCID: PMC3583697.

63. Lof-Ohlin ZM, Sorbe B, Wingren S, Nilsson TK. Hypermethylation of promoter regions of the APC1A and p16(INK4a) genes in relation to prognosis and tumor characteristics in cervical cancer patients. International Journal of Oncology. 2011;39(3):683–8. doi: 10.3892/ijo.2011.1078 WOS:000293492900018. 21674126

64. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemporary clinical trials. 2007;28(2):105–14. Epub 2006/06/30. doi: 10.1016/j.cct.2006.04.004 16807131.

65. Lee H, Lee EJ. HPV infection and p16 promoter methylation as predictors of ASC-US/LSIL progression. Cancer cytopathology. 2016;124(1):58–65. Epub 2015/09/04. doi: 10.1002/cncy.21615 26335500.

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