Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix

Abstract

Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations.

Figure 1

Progression of cervical cancer by HPV and promoter methylation during progression. Adapted from Woodman et al., 2007 [5]. The HPV virus has access to the basal cells by means of microlesions present in the cervical tissue. The virus is maintained in episomic form with a low number of copies (cells with a purple nucleus). The cells of the basal layer are divided and begin to migrate towards the surface. The untreated lesions progress to microinvasive and invasive cancer, where the HPV genome is associated with the host genome (cells with red nuclei). In the superficial layer the viral DNA is packed in capsids and the progeny is released to reinitiate the infection.