DNA甲基化预测宫颈癌及癌前病变的研究进展

doi:10.12280/gjfckx.20230135

摘要/Abstract

摘要：

近年来随着早期筛查的普及，我国的宫颈癌发病率及死亡率均有所下降，细胞学检查及高危型人乳头瘤病毒（human papilloma virus，HPV）检测是目前常用的宫颈癌筛查手段，但二者均有局限性，细胞学检查可能导致疾病漏诊，而高危型HPV检测常导致过度诊疗，因此，探索一种新的宫颈癌筛查或分流手段十分必要。DNA甲基化是一种常见的表观遗传方式，随着DNA甲基化检测技术的发展，其在肿瘤诊疗领域发挥越来越大的作用。近年来发现许多甲基化基因可作为宫颈癌标志物，在宫颈癌筛查及分流方面具有应用前景，并且具有预测疾病转归、采样方便等优势，有利于宫颈癌的早期诊断及治疗。综述DNA甲基化在宫颈癌及宫颈癌前病变中的相关研究进展。

关键词: DNA甲基化, 宫颈肿瘤, 癌前状态, 癌症早期检测, 乳头状瘤病毒科

Abstract:

In recent years, with the popularization of early screening, the incidence and mortality rate of cervical cancer in China have decreased. Cytological examination and high-risk human papilloma virus(HPV) test are common screening methods for cervical cancer at present, but they both have their limitations. Cytological examination may lead to missed diagnosis, while high-risk HPV test may lead to over-diagnosis and over-treatment. Therefore, it is necessary to explore a new screening or triage method for cervical cancer. DNA methylation is a common epigenetic modality. With the development of DNA methylation detection technology, DNA methylation has played an increasingly important role in the field of oncology diagnosis and treatment. In recent years, a large amount of DNA methylation genes has been found as markers of cervical cancer, which have a promising application in cervical cancer screening and triage, and have the advantages of prognosis prediction and convenient sampling. DNA methylation is beneficial for the early diagnosis and treatment of cervical cancer. This article reviews the research progress of DNA methylation in cervical cancer and precancerous lesions.

Key words: DNA methylation, Uterine cervical neoplasms, Precancerous conditions, Early detection of cancer, Papillomaviridae

吴若兰, 邱丽华. DNA甲基化预测宫颈癌及癌前病变的研究进展[J]. 国际妇产科学杂志, 2023, 50(3): 281-285.

WU Ruo-Lan, QIU Li-hua. Research Progress on DNA Methylation in Predicting Cervical Cancer and Precancerous Lesions[J]. Journal of International Obstetrics and Gynecology, 2023, 50(3): 281-285.

参考文献 37

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660. doi: 10.3322/caac.21660
[2]	Bedell SL, Goldstein LS, Goldstein AR, et al. Cervical Cancer Screening: Past, Present, and Future[J]. Sex Med Rev, 2020, 8(1):28-37. doi: 10.1016/j.sxmr.2019.09.005. doi: S2050-0521(19)30101-5 pmid: 31791846
[3]	Nebbioso A, Tambaro FP, Dell′Aversana C, et al. Cancer epigenetics: Moving forward[J]. PLoS Genet, 2018, 14(6):e1007362. doi: 10.1371/journal.pgen.1007362. doi: 10.1371/journal.pgen.1007362
[4]	Laird PW. The power and the promise of DNA methylation markers[J]. Nat Rev Cancer, 2003, 3(4):253-266. doi: 10.1038/nrc1045. doi: 10.1038/nrc1045 pmid: 12671664
[5]	Wu W, Kong X, Jia Y, et al. An overview of PAX1: Expression, function and regulation in development and diseases[J]. Front Cell Dev Biol, 2022, 10:1051102. doi: 10.3389/fcell.2022.1051102. doi: 10.3389/fcell.2022.1051102
[6]	Su PH, Lai HC, Huang RL, et al. Paired Box-1(PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer[J]. Sci Rep, 2019, 9(1):9195. doi: 10.1038/s41598-019-45477-5. doi: 10.1038/s41598-019-45477-5
[7]	Luan T, Hua Q, Liu X, et al. PAX1 Methylation as a Potential Biomarker to Predict the Progression of Cervical Intraepithelial Neoplasia: A Meta-analysis of Related Studies[J]. Int J Gynecol Cancer, 2017, 27(7):1480-1488. doi: 10.1097/IGC.0000000000001011. doi: 10.1097/IGC.0000000000001011 pmid: 28472814
[8]	Nikolaidis C, Nena E, Panagopoulou M, et al. PAX1 methylation as an auxiliary biomarker for cervical cancer screening: a meta-analysis[J]. Cancer Epidemiol, 2015, 39(5):682-686. doi: 10.1016/j.canep.2015.07.008. doi: 10.1016/j.canep.2015.07.008 pmid: 26234429
[9]	Zhang L, Yu J, Huang W, et al. A Sensitive and Simplified Classifier of Cervical Lesions Based on a Methylation-Specific PCR Assay: A Chinese Cohort Study[J]. Cancer Manag Res, 2020, 12:2567-2576. doi: 10.2147/CMAR.S246103. doi: 10.2147/CMAR.S246103 pmid: 32346310
[10]	Li T, Wang W, Cheng Y, et al. Method for quantitative detection of FAM19A4 by flow cytometry using latex beads as solid carrier[J]. J Biosci Bioeng, 2018, 125(3):359-364. doi: 10.1016/j.jbiosc.2017.10.008. doi: S1389-1723(17)30712-0 pmid: 29167066
[11]	Steenbergen RD, Ongenaert M, Snellenberg S, et al. Methylation-specific digital karyotyping of HPV16E6E7-expressing human keratinocytes identifies novel methylation events in cervical carcinogenesis[J]. J Pathol, 2013, 231(1):53-62. doi: 10.1002/path.4210. doi: 10.1002/path.4210
[12]	Wilting SM, van Boerdonk RA, Henken FE, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer[J]. Mol Cancer, 2010, 9:167. doi: 10.1186/1476-4598-9-167. doi: 10.1186/1476-4598-9-167 pmid: 20579385
[13]	Vink FJ, Meijer C, Clifford GM, et al. FAM19A4/miR124-2 methylation in invasive cervical cancer: A retrospective cross-sectional worldwide study[J]. Int J Cancer, 2020, 147(4):1215-1221. doi: 10.1002/ijc.32614. doi: 10.1002/ijc.32614 pmid: 31390052
[14]	Bonde J, Floore A, Ejegod D, et al. Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study[J]. Int J Cancer, 2021, 148(2):396-405. doi: 10.1002/ijc.33320. doi: 10.1002/ijc.33320
[15]	Hansel A, Steinbach D, Greinke C, et al. A promising DNA methylation signature for the triage of high-risk human papillomavirus DNA-positive women[J]. PLoS One, 2014, 9(3):e91905. doi: 10.1371/journal.pone.0091905. doi: 10.1371/journal.pone.0091905
[16]	Schmitz M, Wunsch K, Hoyer H, et al. Performance of a methylation specific real-time PCR assay as a triage test for HPV-positive women[J]. Clin Epigenetics, 2017, 9:118. doi: 10.1186/s13148-017-0419-2. doi: 10.1186/s13148-017-0419-2 pmid: 29090037
[17]	Zhang L, Zhao X, Hu S, et al. Triage performance and predictive value of the human gene methylation panel among women positive on self-collected HPV test: Results from a prospective cohort study[J]. Int J Cancer, 2022, 151(6):878-887. doi: 10.1002/ijc.34041. doi: 10.1002/ijc.34041 pmid: 35460075
[18]	Dippmann C, Schmitz M, Wunsch K, et al. Triage of hrHPV-positive women: comparison of two commercial methylation-specific PCR assays[J]. Clin Epigenetics, 2020, 12(1):171. doi: 10.1186/s13148-020-00963-w. doi: 10.1186/s13148-020-00963-w pmid: 33176878
[19]	向睿, 叶礼翠, 孟侠, 等. 宫安丽多基因甲基化检测在宫颈癌筛查风险分层管理中的价值[J]. 中国煤炭工业医学杂志, 2021, 24(1):59-62. doi: 10.11723/mtgyyx1007-9564 202101014.
[20]	孙文雄. 宿主多基因甲基化检测在宫颈病变诊断中的应用价值[D]. 济南: 山东大学, 2022.
[21]	黄革. 宿主基因甲基化检测对高危型HPV分流的临床研究[D]. 长春: 吉林大学, 2021.
[22]	Salta S, Maia-Moço L, Estevão-Pereira H, et al. Performance of DNA methylation-based biomarkers in the cervical cancer screening program of northern Portugal: A feasibility study[J]. Int J Cancer, 2021, 149(11):1916-1925. doi: 10.1002/ijc.33778. doi: 10.1002/ijc.33778 pmid: 34460099
[23]	Su Y, Tang Y, Zhang T, et al. Methylated ZNF582 as a triage marker for occult cervical cancer and advanced cervical intraepithelial neoplasia[J]. Future Oncol, 2022, 18(23):2583-2592. doi: 10.2217/fon-2021-1625. doi: 10.2217/fon-2021-1625
[24]	Huang J, Gao H, Tan HZ. SOX1 Promoter Hypermethylation as a Potential Biomarker for High-Grade Squamous Intraepithelial Neoplasia Lesion and Cervical Carcinoma: A Meta-Analysis With Trial Sequential Analysis[J]. Front Genet, 2020, 11:633. doi: 10.3389/fgene.2020.00633. doi: 10.3389/fgene.2020.00633 pmid: 32849763
[25]	Chujan S, Kitkumthorn N, Siriangkul S, et al. CCNA1 promoter methylation: a potential marker for grading Papanicolaou smear cervical squamous intraepithelial lesions[J]. Asian Pac J Cancer Prev, 2014, 15(18):7971-7975. doi: 10.7314/apjcp.2014.15.18.7971. doi: 10.7314/apjcp.2014.15.18.7971
[26]	Oranratanaphan S, Kengsakul M, Triratanachat S, et al. CyclinA1 Promoter Methylation in Self-Sampling Test[J]. Asian Pac J Cancer Prev, 2020, 21(10):2913-2917. doi: 10.31557/APJCP.2020.21.10.2913. doi: 10.31557/APJCP.2020.21.10.2913
[27]	Oranratanaphan S, Kobwitaya K, Termrungruanglert W, et al. Value of CCNA1 promoter methylation in triaging ASC-US cytology[J]. Asian Pac J Cancer Prev, 2020, 21(2):473-477. doi: 10.31557/APJCP.2020.21.2.473. doi: 10.31557/APJCP.2020.21.2.473
[28]	Chao TK, Ke FY, Liao YP, et al. Triage of cervical cytological diagnoses of atypical squamous cells by DNA methylation of paired boxed gene 1 (PAX1)[J]. Diagn Cytopathol, 2013, 41(1):41-46. doi: 10.1002/dc.21758. doi: 10.1002/dc.21758
[29]	De Strooper L, Berkhof J, Steenbergen R, 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[J]. Int J Cancer, 2018, 143(6):1541-1548. doi: 10.1002/ijc.31539. doi: 10.1002/ijc.31539 pmid: 29663363
[30]	Dick S, Kremer WW, De Strooper L, et al. Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis[J]. Gynecol Oncol, 2019, 154(2):368-373. doi: 10.1016/j.ygyno.2019.06.002. doi: S0090-8258(19)31279-X pmid: 31182225
[31]	Kremer WW, Dick S, Heideman D, et al. Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)[J]. J Clin Oncol, 2022, 40(26):3037-3046. doi: 10.1200/JCO.21.02433. doi: 10.1200/JCO.21.02433
[32]	Vink FJ, Meijer C, Hesselink AT, et al. FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus(HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years[J]. Clin Infect Dis, 2023, 76(3):e827-e834. doi: 10.1093/cid/ciac433. doi: 10.1093/cid/ciac433
[33]	伍恒英, 彭苏珺, 布俏雯, 等. FAM19A4基因启动子甲基化在高危型HPV阴性宫颈癌诊断中的作用[J]. 实用医学杂志, 2019, 35(5):683-687. doi: 10.3969/j.issn.1006-5725.2019.05.002. doi: 10.3969/j.issn.1006-5725.2019.05.002
[34]	Schmitz M, Eichelkraut K, Schmidt D, et al. Performance of a DNA methylation marker panel using liquid-based cervical scrapes to detect cervical cancer and its precancerous stages[J]. BMC Cancer, 2018, 18(1):1197. doi: 10.1186/s12885-018-5125-8. doi: 10.1186/s12885-018-5125-8 pmid: 30509219
[35]	Leffers M, Herbst J, Kropidlowski J, et al. Combined Liquid Biopsy Methylation Analysis of CADM1 and MAL in Cervical Cancer Patients[J]. Cancers (Basel), 2022, 14(16):3954. doi: 10.3390/cancers14163954. doi: 10.3390/cancers14163954
[36]	van den Helder R, Steenbergen R, van Splunter AP, et al. HPV and DNA Methylation Testing in Urine for Cervical Intraepithelial Neoplasia and Cervical Cancer Detection[J]. Clin Cancer Res, 2022, 28(10):2061-2068. doi: 10.1158/1078-0432.CCR-21-3710. doi: 10.1158/1078-0432.CCR-21-3710 pmid: 35266975
[37]	Rohner E, McGuire FH, Liu Y, et al. Racial and Ethnic Differences in Acceptability of Urine and Cervico-Vaginal Sample Self-Collection for HPV-Based Cervical Cancer Screening[J]. J Womens Health(Larchmt), 2020, 29(7):971-979. doi: 10.1089/jwh.2019.8132. doi: 10.1089/jwh.2019.8132