Abstract
BackgroundHuman papillomavirus (HPV) inactivates the retinoblastoma 1 (RB1) gene by promoter methylation and reduces cellular E-cadherin expression by overexpression of DNA methyltransferase 1 (DNMT1). The Epstein-Barr virus (EBV) is an oncogenic virus that may be related to cervical carcinogenesis. In gastric cancer, it has been demonstrated that E-cadherin gene (CDH1) hypermethylation is associated with DNMT1 overexpression by EBV infection. Our aim was to analyze the gene promoter methylation frequency of RB1 and CDH1 and verify the association between that methylation frequency and HPV and EBV infection in cervical lesions.MethodsSixty-five samples were obtained from cervical specimens: 15 normal cervices, 17 low-grade squamous intraepithelial lesions (LSIL), 15 high-grade squamous intraepithelial lesions (HSIL), and 18 cervical cancers. HPV and EBV DNA testing was performed by PCR, and the methylation status was verified by MSP.ResultsHPV frequency was associated with cervical cancer cases (p = 0.005) but not EBV frequency (p = 0.732). Viral co-infection showed a statistically significant correlation with cancer (p = 0.027). No viral infection was detected in 33.3% (5/15) of controls. RB1 methylated status was associated with cancer (p = 0.009) and HPV infection (p = 0.042). CDH1 methylation was not associated with cancer (p = 0.181). Controls and LSIL samples did not show simultaneous methylation, while both genes were methylated in 27.8% (5/18) of cancer samples. In the presence of EBV, CDH1 methylation was present in 27.8% (5/18) of cancer samples. Only cancer cases presented RB1 promoter methylation in the presence of HPV and EBV (33.3%).ConclusionsThe methylation status of both genes increased with disease progression. With EBV, RB1 methylation was a tumor-associated event because only the cancer group presented methylated RB1 with HPV infection. HPV infection was shown to be significantly correlated with cancer conditions. The global methylation frequency was higher when HPV was present, showing its epigenetic role in cervical carcinogenesis. Nevertheless, EBV seems to be a cofactor and needs to be further investigated.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1159157579149317.
Highlights
Human papillomavirus (HPV) inactivates the retinoblastoma 1 (RB1) gene by promoter methylation and reduces cellular E-cadherin expression by overexpression of DNA methyltransferase 1 (DNMT1)
The control samples were obtained from 15 cervical specimens with normal cytology and colposcopy, and 50 patients showing prior cytology with cervical lesions were classified by its cytological alterations as follows: 17 low-grade squamous intraepithelial lesions (LSILs), 15 high-grade squamous intraepithelial lesions (HSILs), and 18 cervical cancers
HPV and Epstein-Barr virus (EBV) detection HPV DNA was detected in 26.6% (4/15) of control samples, while among the case samples, this frequency was 66.0% (33/50), 64.4% (11/17) of LSIL cases, 53.3% (8/15) of HSIL cases and 77.8% (14/18) of cervical cancer samples
Summary
Human papillomavirus (HPV) inactivates the retinoblastoma 1 (RB1) gene by promoter methylation and reduces cellular E-cadherin expression by overexpression of DNA methyltransferase 1 (DNMT1). It has been demonstrated that E-cadherin gene (CDH1) hypermethylation is associated with DNMT1 overexpression by EBV infection. Our aim was to analyze the gene promoter methylation frequency of RB1 and CDH1 and verify the association between that methylation frequency and HPV and EBV infection in cervical lesions. Cervical cancer represents an important public health problem, as it is the fourth most common type of carcinoma in women worldwide. This disease was responsible for 265,000 deaths in 2012, of which 87% occurred in developing countries [1]. Genital human papillomavirus (HPV) infection causes virtually all cervical cancer cases [3], and the factors correlated with development from the initial lesion to invasive carcinoma are poorly understood [4]. Among the high-risk HPVs (HR-HPV), HPV16 is of major clinical importance, causing over 50% of cervical cancer cases [6]
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