Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Hesselink, Albertus T.; Heideman, Daniëlle A.M.; Steenbergen, Renske D.M.; Coupé, Veerle M.H.; Overmeer, René M.; Rijkaart, Dorien; Berkhof, Johannes; Meijer, Chris J.L.M.; Snijders, Peter J.F.

doi:10.1158/1078-0432.ccr-10-2548

Cited by 125 publications

(205 citation statements)

References 37 publications

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“…Moreover, prior knowledge of hrHPV-positivity influences cytology reading, which may result in an increase of false-positive referrals with simultaneously higher costs for the healthcare system [47–49]. Recent clinical validation studies in screening populations have shown that DNA methylation markers provide a good alternative for cytology [14,50–54]. …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis. DNA methylation analysis was performed by quantitative methylation-specific PCR (qMSP) and relative qMSP values were used to analyze the data. The majority of genes displayed a comparable DNA methylation pattern in both cell lines and clinical specimens. DNA methylation onset occurred at early or late immortal passage, and DNA methylation levels gradually increased towards tumorigenic cells. Subsequently, we defined a so-called cancer-like methylation-high pattern based on the DNA methylation levels observed in cervical scrapings from women with cervical cancer. This cancer-like methylation-high pattern was observed in 72% (38/53) of CIN3 and 55% (11/20) of CIN2, whereas it was virtually absent in hrHPV-positive controls (1/26). In conclusion, hrHPV-induced carcinogenesis is characterized by early onset of DNA methylation, typically occurring at the pre-tumorigenic stage and with highest DNA methylation levels at the cancer stage. Host-cell DNA methylation patterns in cervical scrapings from women with CIN2 and CIN3 are heterogeneous, with a subset displaying a cancer-like methylation-high pattern, suggestive for a higher cancer risk.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Of 1,040 HPV‐positive women, sufficient left‐over material of baseline cervical scrapes was available and valid FAM19A4/mir124‐2 methylation test results were obtained. DNA from cervical scrapes was isolated using the Nucleo‐Spin 96 Tissue kit (Macherey‐Nagel, Duren, Germany) and a Microlab Star robotic system (Hamilton, Planegg, Germany) according to manufacturers’ protocol 32. Extracted DNA was subjected to bisulphite treatment using the EZ DNA Methylation Kit (Zymo Research, Irvine, CA) as described previously 33, 34.…”

Section: Methodsmentioning

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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“…17 The isolated DNA was subjected to general primers 5+/6+ PCR-enzyme immunoassay (GP5+/6+; Diassay, The Netherlands). 18 A microsphere bead-based assay (Luminex) 19 was used for genotyping of the high-risk …”

Section: Hpv Testing and Genotypingmentioning

confidence: 99%

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

et al. 2016

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Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥ CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n = 446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopybased triage tool for high-risk HPV-positive women. Persistent infection with a high-risk type of the human papillomavirus (HPV) is essential for the development of almost all cervical cancers. 1,2 Testing for high-risk HPV has been shown to provide superior protection against cervical intraepithelial neoplasia grade 3 and cervical cancer (together referred to as ≥ CIN3) compared with cervical cytology (Pap cytology). 3 However, most women who test positive for high-risk HPV clear the virus spontaneously and do not develop clinically relevant cervical disease. Therefore, additional triage testing is required to identify the subgroup of high-risk HPVpositive women who actually have ≥ CIN3, thereby Correspondence: Professor CJLM Meijer, MD PhD,

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Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Cited by 125 publications

References 37 publications

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

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

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

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

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