Document Type : Original Article(s)
Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran
Background: Cervical cancer (CC) is the second most common type of cancer among women. A key factor in developing the disease is the human papillomavirus (HPV) infection. Aberrant DNA hypermethylation in gene promoter regions is one of the most well-fined epigenetic alterations in tumors. This study aimed to investigate cell adhesion molecule 1 (CADM1), promoter methylation in HPV serological positive samples in the Iranian population.
Method: Genomic DNA was extracted from cervical smears from patients and healthy patients acting as a control group for this analytical observational case-control investigation. Reverse dot blotting was performed to first identify the presence of HPV DNA infection. After that, each sample was transformed by being treated with sodium bisulfite, and MSP was then used to determine the CADM1 gene's level of methylation.
Results: Among total number of positive HPV samples (n = 52), 63.5% methylated, 23% hemi-methylated, and 13.5% were unmethylated. On the contrary, in the control group (n=38), 11% methylated, 71% hemi-methylated, and 18% were unmethylated (P < 0.0001). Furthermore, comparing the methylation status among high, low and high/low patients indicated that methylation was (66.66, 24.24, and 9.09%), (25, 66.66, and 8.33%), and (14.28, 57.14%, and 28.57%), respectively (P < 0.0001).
Conclusion: The present study confirmed that the methylation status of CADM1 gene was significantly higher in HPV-positive patients than in patients negative for HPV DNA. Moreover, the CADM1 pattern of the gene was associated with the highrisk subtypes of HPV, not with the low-risk ones. Therefore, CADM1 methylation appeared to be a promising biomarker for future studies.
How to cite this article:
Jalili F, Asaadi Tehrani G, Mirzaahamdi S. Evaluation of CAMD1 gene promoter hypermethylation in human papillomavirus positive cytological samples of cervical cancer. Middle East J Cancer. 2023;14(2):250-8. doi: 10. 30476/mejc.2022.93587.1691.
- Catarino R, Petignat P, Dongui G, Vassilakos P. Cervical cancer screening in developing countries at a crossroad: Emerging technologies and policy choices. World J Clin Oncol. 2015;6(6):281-90. doi: 10.5306/wjco.v6.i6.281.
- Momenimovahed Z, Salehiniya H. Cervical cancer in Iran: integrative insights of epidemiological analysis. Biomedicine (Taipei). 2018;8(3):18. doi: 10.1051/bmdcn/2018080318.
- Song B, Ding C, Chen W, Sun H, Zhang M, Chen W. Incidence and mortality of cervical cancer in China, 2013. Chin J Cancer Res. 2017;29(6):471-6. doi: 10.21147/j.issn.1000-9604.2017.06.01.
- Roura E, Castellsague X, Pawlita M, Travier N, Waterboer T, Margall N, et al. Smoking as a major risk factor for cervical cancer and pre-cancer: results from the EPIC cohort. Int J Cancer. 2014;135(2):453-66. doi: 10.1002/ijc.28666.
- Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: Past, present and future. Gynecol Oncol Rep. 2017;21:101-8. doi: 10.1016/j.gore.2017.07.009.
- Sanford NN, Sher DJ, Butler S, Xu X, Ahn C, D'Amico AV, et al. Cancer screening patterns among current, former, and never smokers in the United States, 2010-2015. JAMA Netw Open. 2019;2(5):e193759. doi:10.1001/jamanetworkopen.2019.3759.
- Athanasiou A, Bowden S, Paraskevaidi M, Fotopoulou C, Martin-Hirsch P, Paraskevaidis E, et al. HPV vaccination and cancer prevention. Best Pract Res Clin Obstet Gynaecol. 2020;65:109-24.doi: 10.1016/j.bpobgyn.2020.02.009.
- McBride AA. Mechanisms and strategies of papillomavirus replication. Biol Chem. 2017;398(8):919-27. doi: 10.1515/hsz-2017-0113.
- Tommasino M. The human papillomavirus family and its role in carcinogenesis. Semin Cancer Biol. 2014;26:13-21. doi: 10.1016/j.semcancer.2013.11.002.
- Heidegger I, Borena W, Pichler R. The role of human papilloma virus in urological malignancies. Anticancer Res. 2015;35(5):2513-9.
- Klingelhutz AJ, Roman A. Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses. Virology. 2012;424(2):77-98. doi: 10.1016/j.virol.2011.12.018.
- Yin FF, Wang N, Bi XN, Yu X, Xu XH, Wang YL, et al. Serine/threonine kinases 31(STK31) may be a novel cellular target gene for the HPV16 oncogene E7 with potential as a DNA hypomethylation biomarker in cervical cancer. Virol J. 2016;13:60. doi: 10.1186/s12985-016-0515-5.
- Lin H, Ma Y, Wei Y, Shang H. Genome-wide analysis of aberrant gene expression and methylation profiles reveals susceptibility genes and underlying mechanism of cervical cancer. Eur J Obstet Gynecol Reprod Biol. 2016;207:147-52. doi: 10.1016/j.ejogrb.2016.10.017.
- Lafage-Pochitaloff M, Gerby B, Baccini V, Largeaud L, Fregona V, Prade N, et al. The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11. Blood Adv. 2022;6(2):386-98. doi: 10.1182/bloodadvances.2021005311.
- Giangreco A, Hoste E, Takai Y, Rosewell I, Watt FM. Epidermal CADM1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity. J Immunol. 2012;188(3):1514-22. doi: 10.4049/jimmunol.1003342.
- Li Y, Wang G, Wang Q, Zhang Y, Cui L, Huang X. Exosomes secreted from adipose-derived stem cells are a potential treatment agent for immune-mediated alopecia. J Immunol Res. 2022;2022:7471246. doi:10.1155/2022/7471246.
- Overmeer RM, Henken FE, Snijders PJ, Claassen-Kramer D, Berkhof J, Helmerhorst TJ, et al. Association between dense CADM1 promoter methylation and reduced protein expression in high-grade CIN and cervical SCC. J Pathol. 2008;215(4):388-97. doi:10.1002/path.2367.
- Baci D, Bosi A, Parisi L, Buono G, Mortara L, Ambrosio G, et al. Innate immunity effector cells as inflammatory drivers of cardiac fibrosis. Int J Mol Sci. 2020;21(19):7165. doi: 10.3390/ijms21197165.
- Kawano S, Ikeda W, Kishimoto M, Ogita H, Takai Y. Silencing of ErbB3/ErbB2 signaling by immunoglobulin-like Necl-2. J Biol Chem. 2009;284(35):23793-805. doi: 10.1074/jbc.M109.025155.
- De Santis MC, Sala V, Martini M, Ferrero GB, Hirsch E. PI3K signaling in tissue hyper-proliferation: From overgrowth syndromes to kidney cysts. Cancers (Basel). 2017;9(4):30. doi: 10.3390/cancers9040030.
- Pal A, Kundu R. Human papillomavirus E6 and E7: The cervical cancer hallmarks and targets for therapy. Front Microbiol. 2020;10:3116. doi: 10.3389/fmicb.2019.03116.
- Yuan BF. 5-methylcytosine and its derivatives. Adv Clin Chem. 2014;67:151-87. doi: 10.1016/bs.acc.2014.09.003.
- Williams K, Christensen J, Helin K. DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep. 2011;13(1):28-35. doi: 10.1038/embor.2011.233.
- Wu EQ, Liu B, Cui JF, Chen W, Wang JB, Lu L, et al. Prevalence of type-specific human papillomavirus and pap results in Chinese women: a multi-center, population-based cross-sectional study. Cancer Causes Control. 2013;24(4):795-803. doi: 10.1007/s10552-013-0162-8.
- Cuschieri K, Ronco G, Lorincz A, Smith L, Ogilvie G, Mirabello L, et al. Eurogin roadmap 2017: Triage strategies for the management of HPV-positive women in cervical screening programs. Int J Cancer. 2018;143(4):735-45. doi: 10.1002/ijc.31261.
- Wentzensen N, Sherman ME, Schiffman M, Wang SS. Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol. 2009;112(2):293-9. doi: 10.1016/j.ygyno.2008.10.012.
- Zhang W, Xie HY, Ding SM, Xing CY, Chen A, Lai MC, et al. CADM1 regulates the G1/S transition and represses tumorigenicity through the Rb-E2F pathway in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2016;15(3):289-96. doi: 10.1016/s1499-3872(16)60099-1.
- Meršakova S, Holubekova V, Grendar M, Višňovsky J, Ňachajova M, Kalman M, et al. Methylation of CADM1 and MAL together with HPV status in cytological cervical specimens serves an important role in the progression of cervical intraepithelial neoplasia. Oncol Lett. 2018;16(6):7166-74. doi:10.3892/ol.2018.9505.
- Dankai W, Khunamornpong S, Siriaunkgul S, Soongkhaw A, Janpanao A, Utaipat U, et al. Role of genomic DNA methylation in detection of cytologic and histologic abnormalities in high risk HPV-infected women. PLoS One. 2019;14(1):e0210289. doi:10.1371/journal.pone.0210289.
- van den Berg RM, Snijders PJ, Grunberg K, Kooi C, Spreeuwenberg MD, Meijer CJ, Pet al. Comprehensive CADM1 promoter methylation analysis in NSCLC and normal lung specimens. Lung Cancer. 2011;72(3):316-21. doi: 10.1016/j.lungcan.2010.10.005.
- Hassan ZK, Hafez MM, Kamel MM, Zekri AR. Human papillomavirus genotypes and methylation of CADM1, PAX1, MAL and ADCYAP1 genes in epithelial ovarian cancer patients. Asian Pac J Cancer Prev. 2017;18(1):169-76. doi: 10.22034/APJCP.2017.18.1.169.