DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women

Boers, Aniek; Bosgraaf, Remko P.; Leeuwen, Robert W. van; Schuuring, Ed; Heideman, Daniëlle A.M.; Massuger, Leon F.A.G.; Verhoef, Viola M.J.; Bulten, Johan; Melchers, Willem J. G.; Zee, Ate G.J. van der; Bekkers, Ruud L.M.; Wisman, G. Bea A.

doi:10.1038/bjc.2014.392

Cited by 59 publications

(63 citation statements)

References 46 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Strooper

Berkhof

Steenbergen

et al. 2018

Intl Journal of Cancer

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DNA methylation analysis of cervical scrapes using FAM19A4 and mir124‐2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV‐positive women. To date, longitudinal data on the cancer risk of methylation test‐negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124‐2 methylation analysis in an HPV‐positive screening cohort with 14 years of follow‐up. Archived HPV‐positive cervical scrapes of 1,040 women (age 29–61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124‐2 methylation. By linkage with the nationwide network and registry of histo‐ and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow‐up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124‐2 methylation, including 24 women with cervical cancer in follow‐up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow‐up. Within screening round capability of FAM19A4/mir124‐2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5–100). Kaplan–Meier estimate of 14‐year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66–3.0) among baseline methylation‐negative and 2.4% (95% CI: 1.4–3.6) among baseline cytology‐negative women (risk difference: 0.71% [95% CI: 0.16–1.4]). In conclusion, a negative FAM19A4/mir124‐2 methylation test provides a low cervical cancer risk in HPV‐positive women of 30 years and older. FAM19A4/mir124‐2 methylation testing merits consideration as an objective triage test in HPV‐based cervical screening programs.

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Section: Introductionmentioning

confidence: 99%

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

Strooper

Berkhof

Steenbergen

et al. 2018

Intl Journal of Cancer

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“…Methylation levels of certain host cell genes (such as CADM1, MAL, mir124-2, JAM3, TERT, C13ORF, EPB41L3, ANKRD18CP, GFRA1, CDH6, LHX8, GATA4, PRDM14, and FAM19A4) in cervical scrapes have been shown to increase with the severity of underlying cervical (pre)cancer [51,[95][96][97][98][99]. Furthermore, host cell methylation analysis of CADM1, MAL, mir124-2, and FAM19A4 in cervical scrapes allows the discrimination of high-grade CIN with a long-term preceding hrHPV-infection from those with a short-term hrHPV infection [95,96].…”

Section: 22mentioning

confidence: 99%

“…Therefore, host cell DNA methylation analysis might be of value as a marker for the detection of cervical (pre)cancer among hrHPV-positive women [32,92]. A variety of methylation markers has been studied in clinical cohorts of hrHPVpositive women [51,80,81,96,97,99,[102][103][104][105][106]. In general, these studies were cross-sectional or had a short-term follow-up and the majority of studies were performed in nonscreening cohorts.…”

Section: 22mentioning

confidence: 99%

“…Methylation analysis of JAM3 has been clinically evaluated in hrHPV-positive cohorts of non-attendees [97] and women referred to colposcopy [99,104,105], with a sensitivity for ≥CIN3 ranging between 70.0% and 86.0% and a specificity of 73.0-88.0% (Table 1). In a cross-sectional study design, the NPV was estimated at 93.8-94.8% (Table 1) [105].…”

Section: 22mentioning

confidence: 99%

“…In a cross-sectional study design, the NPV was estimated at 93.8-94.8% (Table 1) [105]. Methylation analysis of the single host genes TERT, C13ORF18, or EPB41L3 for triage of hrHPV-positive women had a more variable accuracy (Table 1) [97,104].…”

Section: 22mentioning

confidence: 99%

See 2 more Smart Citations

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

Luttmer

Strooper

Steenbergen

et al. 2016

Expert Review of Molecular Diagnostics

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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

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Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

Cuschieri

Ronco²,

Lörincz

et al. 2018

Intl Journal of Cancer

142

150

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Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.

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DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women

Cited by 59 publications

References 46 publications

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 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

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

Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

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