The Role of Methylation of Host and/or Human Papillomavirus (HPV) DNA in Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) Lesions

Abstract

Cervical intraepithelial neoplasia grade 2 (CIN2) is an intermediate stage between CIN 1, which is a low-grade lesion, and CIN3, which is the immediate precursor of cervical cancer (CC). Traditionally, CIN2 was regarded as a high-grade lesion and was treated with conization or ablative methods. In recent years, there has been a shift in the management of younger patients, who are now more often being managed conservatively due to frequent spontaneous CIN2 regression and possible adverse effects of treatment on future pregnancies. Because the risk of progression to CC still exists with conservative management, a personalized approach is needed to identify patients with a higher probability of progression. In this regard, research has focused on the role of host and human papillomavirus (HPV) gene methylation. This systematic review summarizes the current knowledge regarding conservative CIN2 management focusing on the main methylation markers and its implementation in conservative CIN2 management, and it describes major ongoing longitudinal studies on the subject. The review showed that DNA methylation is an accurate predictor of disease progression and a valid triage tool for HPV-positive women, with CIN2 performing better than triage cytology. Because virtually all CCs are methylation-positive, methylation-negative women at baseline have an extremely low risk of CC.

FAM19A4 and hsa-miR124-2 Double Methylation as Screening for ASC-H- and CIN1 HPV-Positive Women

“…Dovnik and Poljak also reported these results in a recent review. The authors showed that DNA methylation accurately predicts disease progression and is a valid triage tool for HPV-positive women, with CIN2 performing better than triage cytology [ 27 ]. A negative methylation result for both FAM19A4 and hsa-miR-124-2 was associated with a low long-term risk of cervical cancer in a Dutch longitudinal study [ 28 ].…”

The Role of p16/Ki67 Dual Staining in Cervical Cancer Screening

“…DNA methylation is one of the most extensively investigated epigenetic changes that occur in HPV-related cancers [47]. We recently published a review of the literature regarding the use of methylation markers in cervical cancer screening, with a specific focus on CIN2 [48]. Among the most extensively studied genes affected by HPV-induced methylation are host genes such as FAM19A4, miR124, CADM1, MAL, and PAX1 [49,50].…”

Exploring conservative management for cervical intraepithelial neoplasia grade 2 in organised cervical cancer screening programmes: a multicentre study in Italy

“…1 Excisional treatment (recommended for both lesions) 2 is highly effective in curing the lesions, but can pose risks such as preterm birth, premature rupture of membranes, low birth weight. 3 4 In the last decade, a few countries have developed specific guidelines for the conservative management of CIN2 [5][6][7][8] ; young age (below 25-30 years) is among the most used criteria for selecting suitable cases, as regression probability is higher in younger than older women, 5 the risk of progression after treatment is associated to older age at initial excision, 9 and women of childbearing age (15-45 years) benefit most. Active surveillance is performed also in countries lacking guidelines 6 7 10 ; a recent Dutch nationwide survey disclosed that 41% of the women with a histological diagnosis of CIN2 did not undergo excision within 3 months after biopsy.…”