Molecular progression to cervical precancer, epigenetic switch or sequential model?

Abstract

The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the “molecular switch” model, postulates that CIN3 can evolve directly from human papillomavirus (HPV)‐infected normal epithelium without progressing through CIN1 and CIN2. To shed light on this process, we compared DNA methylation of selected human biomarkers and HPV types in two groups of CIN1: CIN1 that were near or adjacent to CIN3 (adjacent‐CIN1) and CIN1 that were the principal lesions with no CIN3 detected (principal‐CIN1). 354 CIN (CIN1 and CIN3) and normal tissue areas were dissected and typed for HPV from 127 women who underwent loop electrosurgical excision procedures (LEEP). Methylation of genes EPB41L3 and the viral regions of HPV16‐L1/L2, HPV18‐L2, HPV31‐L1, and HPV33‐L2 were determined by a highly accurate quantitative pyrosequencing of bisulfite converted DNA. There was a significant trend of increased methylation with disease grade comparing normal to CIN1 and CIN3 (p < 0.0001). Adjacent‐CIN1 predominantly shared the same HPV types as the CIN3, however, methylation differed substantially between adjacent‐CIN1 and CIN3 (p = 0.008). In contrast diagnostically principal‐CIN1 had an indistinguishable methylation distribution compared to adjacent‐CIN1 (EPB41L3: p = 0.49; HPVme‐All: p = 0.11). Our results suggest that progression from normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes, thus favoring the “molecular switch” model.

DNA methylation for cervical cancer screening: a training set in China

“…However, compared with inflammation or CIN1, a significantly increased proportion of hrHPV positivity was found among CIN3 and SCC cases but with similar ratios among endocervical ADC and other malignancies. EPB41L3 methylation and HPV types in CIN1 suggest that progression from a normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes [44].…”

Single type infection of human papillomavirus as a cause for high-grade cervical intraepithelial neoplasia and invasive cancer in Japan

“…These results suggest that HPV18 may induce SCC through the de novo pathway, since the cancer appears to be rapidly developed by HPV18 than other high-risk HPV types. Some studies have suggested that CIN3 may be developed directly from normal epithelium [32] , [33] , [34] . This hypothesis of de novo carcinogenesis by HPV18 warrants further investigation in the future study.…”

Methylation estimates the risk of precancer in HPV-infected women with discrepant results between cytology and HPV16/18 genotyping

“…DNA methylation, the enzymatic addition of a methyl group to the carbon at position 5 of the cytosine ring in a cytosine-phosphate-guanine (CpG) site, has been shown to play an important role in the development of the carcinogenic process [21–25]. Many studies have found a strong association between the methylation of host and viral genome with the development of CIN2, CIN3, and cancer [22, 23, 26–29]. Indeed, various quantitative combination methylation assays are currently under evaluation with the most common host genes being EPB41L3 , MAL , CADM , FAM19A4 , and MIR124 , as well as CpG sites in the late regions of various HPV genomes [24, 30–35].…”