Association between RASSF1A Promoter Hypermethylation and Oncogenic HPV Infection Status in Invasive Cervical Cancer: a Meta-analysis

  • Li, Jin-Yun (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Huang, Tao (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Zhang, Cheng (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Jiang, Dan-Jie (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Hong, Qing-Xiao (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Ji, Hui-Hui (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University) ;
  • Ye, Meng (The Affiliated Hospital, Ningbo University) ;
  • Duan, Shi-Wei (Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University)
  • Published : 2015.09.02


Cervical carcinoma is the main cause of cancer-related mortality in women and is correlated with more than 15 risk cofactors, including infection of cervical cells with high-risk types of HPV (hrHPV). Indeed, both aberrant methylation of the RASSF1A promoter and hrHPV infection are often observed in cervical carcinomas. The purpose of our meta-analysis was to evaluate the role of RASSF1A promoter methylation and hrHPV infection in cervical cancer. Our meta-analysis involved 895 cervical cancer patients and 454 control patients from 15 studies. Our results suggested that RASSF1A promoter hypermethylation increased the risk of cervical cancer (OR=9.77, 95%CI=[3.06, 31.26], P=0.0001, $I^2=78%$). By grouping cases according to cancer subtypes, we found that HPV infection was higher in cervical squamous cell carcinomas (SCCs) than in cervical adenocarcinomas/adenosquamous cancers (ACs/ASCs) (OR=4.00, 95%CI=[1.41, 11.30], P=0.009, $I^2=55%$). Interestingly, HPV infection tended to occur in cervical cancers with relatively low levels of RASSF1A promoter methylation (OR=0.59, 95%CI=[0.36, 0.99], P=0.05, I2=0%). Our study provides evidence of a possible interaction between HPV infection and RASSF1A promoter methylation in the development of cervical cancers.


  1. Yu MY, Tong JH, Chan PK, et al (2003). Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers. Int J Cancer, 105, 204-9.
  2. Zhu X, He F, Zeng H, et al (2014). Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet, 46, 287-93.
  3. Agathanggelou A, Cooper WN, Latif F (2005). Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res, 65, 3497-508.
  4. Bird AP (1986). CpG-rich islands and the function of DNA methylation. Nature, 321, 209-13.
  5. Bosch FX, Manos MM, Munoz N, et al (1995). Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst, 87, 796-802.
  6. Brown TC, Juhlin CC, Healy JM, et al (2014). Frequent silencing of RASSF1A via promoter methylation in follicular thyroid hyperplasia: a potential early epigenetic susceptibility event in thyroid carcinogenesis. JAMA Surg.
  7. Castellsague X (2008). Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol, 110, 4-7.
  8. Cheung TH, Lo KW, Yim SF, et al (2004). Epigenetic and genetic alternation of PTEN in cervical neoplasm. Gynecol Oncol, 93, 621-7.
  9. Cohen Y, Singer G, Lavie O, et al (2003). The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix. Clin Cancer Res, 9, 2981-4.
  10. Farthing AJ, Vousden KH (1994). Functions of human papillomavirus E6 and E7 oncoproteins. Trends Microbiol, 2, 170-4.
  11. Feng L, Li J, Yan LD, et al (2014). RASSF1A suppresses proliferation of cervical cancer cells. Asian Pac J Cancer Prev, 15, 5917-20.
  12. Jha AK, Nikbakht M, Jain V, et al (2012). p16(INK4a) and p15(INK4b) gene promoter methylation in cervical cancer patients. Oncol Lett, 3, 1331-5.
  13. Jiang D, Hong Q, Shen Y, et al (2014a). The diagnostic value of DNA methylation in leukemia: a systematic review and meta-analysis. PLoS One, 9, 96822.
  14. Jiang D, Shen Y, Dai D, et al (2014b). Meta-analyses of methylation markers for prostate cancer. Tumour Biol.
  15. Kuzmin I, Liu L, Dammann R, et al (2003). Inactivation of RAS association domain family 1A gene in cervical carcinomas and the role of human papillomavirus infection. Cancer Res, 63, 1888-93.
  16. Lai HC, Lin YW, Chang CC, et al (2007). Hypermethylation of two consecutive tumor suppressor genes, BLU and RASSF1A, located at 3p21.3 in cervical neoplasias. Gynecol Oncol, 104, 629-35.
  17. Lipsey MW, Wilson DB 2001. Practical meta-analysis, Thousand Oaks, Calif., Sage Publications.
  18. Maliukova AV, Loginov VI, Khodyrev DS, et al (2004). (Methylation of the putative tumor suppressor gene, RASSF1A, in primary cervical tumors). Mol Biol (Mosk), 38, 1005-13.
  19. Munoz N, Bosch FX, de Sanjose S, et al (2003). Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med, 348, 518-27.
  20. Richter AM, Pfeifer GP, Dammann RH (2009). The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta, 1796, 114-28.
  21. Scheffner M, Werness BA, Huibregtse JM, et al (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63, 1129-36.
  22. Shivakumar L, Minna J, Sakamaki T, et al (2002). The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Mol Cell Biol, 22, 4309-18.
  23. van der Weyden L, Adams DJ (2007). The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta, 1776, 58-85.
  24. Walboomers JM, Jacobs MV, Manos MM, et al (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189, 12-9.<12::AID-PATH431>3.0.CO;2-F

Cited by

  1. Promoter methylation of TRIM9 as a marker for detection of circulating tumor DNA in breast cancer patients vol.4, pp.1, 2015,
  2. STAT3 methylation in white blood cells as a novel sensitive biomarker for the toxic effect of low-dose benzene exposure vol.5, pp.3, 2016,
  3. HPV16 oncogenes E6 or/and E7 may influence the methylation status of RASSFIA gene promoter region in cervical cancer cell line HT-3 vol.37, pp.4, 2017,
  4. Comparison of Selected Protein Levels in Tumour and Surgical Margin in a Group of Patients with Oral Cavity Cancer vol.55, pp.4, 2017,