Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Abstract

Introduction: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. Areas covered: Many different colposcopy triage strategies, comprising both microscopy-based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (≥100 hrHPV-positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. ARTICLE HISTORY

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

“…The genes evaluated in this study may well serve as objective molecular tools to improve cervical cancer screening, especially as triage test after primary hrHPV testing [1,7,44]. In several countries, including The Netherlands, hrHPV testing is replacing cytology as primary screening method.…”

“…Increased DNA methylation levels of several (candidate) tumor suppressor genes are associated with cervical cancer and a subset of its high-grade precursor lesions, i.e., cervical intraepithelial neoplasia grade 2 and 3 (CIN2 and CIN3) [1,6,7]. Using both targeted and genome-wide approaches, we previously identified 12 genes, including ANKRD18CP, C13orf18, EPB41L3 , and JAM3 [8,9]; SOX1 and ZSCAN1 [9,10]; GHSR, SST , and ZIC1 [11]; and FAM19A4, PHACTR3 , and PRDM14 [12].…”

“…Using both targeted and genome-wide approaches, we previously identified 12 genes, including ANKRD18CP, C13orf18, EPB41L3 , and JAM3 [8,9]; SOX1 and ZSCAN1 [9,10]; GHSR, SST , and ZIC1 [11]; and FAM19A4, PHACTR3 , and PRDM14 [12]. These genes were considered promising biomarkers to identify hrHPV-positive women and/or women with abnormal cytology at risk for cervical cancer [1,7–14]. …”

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

“…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. In cross‐sectional and short‐term clinical follow‐up studies among both cervical screening and gynecologic outpatient populations, FAM19A4 methylation analysis has shown a similar sensitivity for cervical intraepithelial neoplasia lesions or worse (CIN3+) as compared to cytology 22, 24.…”

A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers

“…More than 180 types of HPV have been identified so far, and each type has evolved to infect and propagate in specific epithelial targets, such as the sole of the foot, non-genital skin, anogenital skin, anogenital mucosa and oropharyngeal mucosa2. Most HPV infections are subclinical and are typically cleared or suppressed by cell-mediated immunity within 1–2 years of exposure.…”