Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions

Abstract

PrefaceInfection of cervical epithelium with high-risk human papillomavirus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN) lesions, the morphology of which can overlap. In transforming CIN lesions aberrations in host cell genes accumulate over time, which is necessary for ultimate progression to cancer. On the basis of (epi)genetic changes, early and advanced transforming CIN lesions can be distinguished. This paves the way for new molecular tools for cervical screening, diagnosis and management of cervical cancer precursor lesions.

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

“…This side‐effect can be tackled by applying an adequate triage test for HPV‐positive women to discern those with clinically relevant disease. Various studies have evaluated triage strategies for HPV‐positive women in screening cohorts, including virus‐ and host cell‐based strategies, such as HPV16/18 genotyping,4, 5 HPV E7 mRNA analysis,6, 7 cytology,8, 9 p16/ki67 dual staining,10, 11 epigenetic changes in the host and/or viral genome,12, 13 and combinations thereof 8, 9. At present, reflex cytology testing, which has been adopted in the Dutch HPV‐based screening program, is considered an appropriate triage test,1, 4, 8, 9, 14 although a short‐term repeat cytology is needed to assure a sufficiently low risk of cervical cancer for triage test‐negative women.…”

“…A candidate, objective triage tool involves DNA hypermethylation analysis of promoter regions of certain host cell genes involved in cervical carcinogenesis 12, 16, 17, 18, 19, 20. Cervical cancer development after a persistent infection with high‐risk HPV is driven by additional host cell changes such as altered DNA methylation 12, 17, 20, 21.…”

“…Cervical cancer development after a persistent infection with high‐risk HPV is driven by additional host cell changes such as altered DNA methylation 12, 17, 20, 21. In earlier work, we have shown that methylation assays targeting FAM19A4 and/or mir124‐2 genes have competitive performance against other triage options 22, 23, 24, 25, 26.…”

“…Those lesions are characterized by a ‘cancer‐like’ (epi)genetic profile and have therefore been considered as advanced precancers 22, 28. Based on this feature, triage testing by methylation analysis has been proposed to confer a high reassurance against short‐term risk of cervical cancer 12. However, longitudinal data on the low cancer risk of methylation test‐negative women are lacking.…”

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

“…Following a persistent infection with a high-risk (hr) type of human papillomavirus (HPV), additional genetic and epigenetic changes in the host cell genome are necessary for progression to cervical cancer [1]. Part of these host cell alterations are induced by expression of viral oncogenes E6 and E7 and include DNA methylation of tumor suppressor genes [2].…”