Evidence map›Paper›PMID 26962367›Full record

ArticleClinical epigenetics2016

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.

A Boers, R Wang, R W van Leeuwen, H G Klip, G H de Bock, H Hollema, W van Criekinge, T de Meyer, S Denil, A G J van der Zee and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical epigenetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed, 1 pooled it
7.9field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

53 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.

  1. Pooled it
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  5. PAX1 and ZNF582 Methylation as a Triage Strategy in Cytologic and hrHPV+ Scrapings in Both Chinese and Dutch Cohorts.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026
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  12. Cytologic DNA methylation for managing minimally abnormal cervical cancer screening results.International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics · 2025
    Article
  13. Identification of a novel hypermethylation marker, ZSCAN18, and construction of a diagnostic model in cervical cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 2 countries.

A BoersDepartment of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
R WangDepartment of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
R W van LeeuwenDepartment of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
H G KlipDepartment of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
G H de BockDepartment of Epidemiology, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
H HollemaDepartment of Pathology, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
W van CriekingeDepartment of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
T de MeyerDepartment of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
S DenilDepartment of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
A G J van der ZeeDepartment of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
E Schuuring *Department of Pathology, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
G B A Wisman *Department of Gynecologic Oncology, internal postal code DA13, Cancer Reserch Center Groningen, University of Groningen, University Medical Center Groningen, PO box 30.001, 9700 RB Groningen, The Netherlands.
University Medical Center Groningen · NLUniversity of Groningen · NLGhent University · BE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundAssessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive.

resultsMethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear.

conclusionsWe identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

Indexed as

AdultCase-Control StudiesCervix UteriDNA MethylationFemaleGenes, NeoplasmGenetic MarkersGenome-Wide Association StudyHumansPapanicolaou TestPolymerase Chain ReactionSensitivity and SpecificityUterine Cervical DysplasiaUterine Cervical NeoplasmsGenetic MarkersCervical cancer screeningCervical precancerous lesionsCervical scrapingDNA methylationHuman papillomavirus (HPV)MethylCap-seqQuantitative methylation-specific PCR (QMSP)

Identifiers

PMID26962367
PMCPMC4784352
OpenAlexW2295468079

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.