Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2021 Jan 15;148(2):396-405.
doi: 10.1002/ijc.33320. Epub 2020 Oct 21.

Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study

Jesper Bonde  1 , Arno Floore  2 , Ditte Ejegod  1 , Frederique J Vink  3 , Albertus Hesselink  2 , Peter M van de Ven  4 , Anja Oštrbenk Valenčak  5 , Helle Pedersen  1 , Saskia Doorn  2 , Wim G Quint  6 , Karl Ulrich Petry  7 , Mario Poljak  5 , Grazyna Stanczuk  8 , Kate Cuschieri  9 , Silvia de Sanjosé  10 , Maaike Bleeker  3 , Johannes Berkhof  4 , Chris J L M Meijer  2   3 , Daniëlle A M Heideman  3
Affiliations
Multicenter Study

Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study

Jesper Bonde et al. Int J Cancer. .

Abstract

In human papillomavirus (HPV) cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicenter, retrospective study conducted to evaluate the clinical performance of the FAM19A4/miR124-2 methylation-based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124-2 methylation test (QIAsure Methylation Test) was evaluated in 2384 HPV-positive cervical screening samples, from women 29-76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV-status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within 2 years of follow-up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen-detected cervical cancers were found methylation-positive (sensitivity 95%). Overall specificity of FAM19A4/miR124-2 methylation test was 78.3% (n = 2013; 95%CI: 76-80). The negative predictive value of hrHPV positive, methylation-negative outcomes were 99.9% for cervical cancer (N = 1694; 95%CI: 99.6-99.99), 96.9% for ≥CIN3 (95%CI: 96-98), and 93.0% for ≥CIN2 (95%CI: 92-94). Overall sensitivity for CIN3 using FAM19A4/miR124-2 methylation test was 77% (n = 228; 95%CI: 71-82). CIN3 sensitivity was uniform between centers independent of sample collection medias, DNA extraction methods and HPV screening tests. Being objectively reported compared to the subjectivity of cytology, equally performing across settings and screening methods, the FAM19A4/miR124-2 methylation constitute an alternative/supplement to cytology as triage method to be investigated in real-life pilot implementation.

Keywords: DNA hypermethylation; biomarker; cervical carcinoma; cervical screening; human genome methylation; human papillomavirus.

PubMed Disclaimer

Conflict of interest statement

The project was funded by the SME Instrument of the European Commission in the HORIZON2020 (Valid‐screen contract ID: 666800).

Jesper Bonde's institution has received research funding or consumables at reduced price or for free to support research from BD Diagnostics, Agena Bioscience, Genomica SAU, LifeRiver Biotech and QIAGEN. He has received honoraria for lectures from BD Diagnostics and Hologic Ltd. Jesper Bonde is an appointed member of the National Danish Cervical Screening Committee by the Danish Health Authority, and a member of the cervical screening steering committee of the Capital Region of Denmark.

Kate Cuschieri institution has received research funding or gratis consumables to support research from the following commercial entities in the last 3 years: Cepheid, Genomica, LifeRiver, Euroimmun, GeneFirst, SelfScreen, Qiagen, Hiantis and Hologic.

Grazyna Stanczuk received diagnostic tests from Roche and travel sponsorship and speaker's fee from Roche and Abbott. DAMH has been on the speaker's bureau of QIAGEN, serves occasionally on the scientific advisory board of Pfizer and Bristol‐Meyers Squibb, and has minority stake in Self‐screen B.V., a spin‐off company of VU University Medical Center (currently known as Amsterdam UMC, Vrije Universiteit Amsterdam). Self‐screen B.V. develops, manufactures and licenses the high‐risk HPV assay and methylation marker assays for cervical cancer screening and holds patents on these tests.

Chris J. L. M. Meijer is minority shareholder and part‐time CEO of Self‐screen B.V., a spin‐off company of VUmc, which develops, manufactures and licenses the high‐risk HPV assay and methylation marker assays for cervical cancer screening and holds patents on these tests. CJLMM has a very small number of shares of QIAGEN and MDXHealth, has received speakers' fees from GSK, QIAGEN, and SPMSD/Merck, and served occasionally on the scientific advisory boards (expert meeting) of these companies.

Anja Oštrbenk Valenčak has received reimbursement of travel expenses for attending conferences and honoraria for speaking from Abbott Molecular, Qiagen and Seegene.

Arno Floore, Saskia Doorn and Albertus Hesselink are employed by Self‐screen B.V.

All other authors report no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Absolute risk plots for CIN3 by hrHPV positive and FAM194A/miR124‐2 methylation‐positive cervical screening samples stratified by concurrent cytology
See this image and copyright information in PMC

References

    1. Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5‐year follow‐up of a randomised controlled implementation trial. Lancet. 2007;370:1764‐1772. - PubMed
    1. Kitchener HC, Almonte M, Gilham C, et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess. 2009;13:1‐150. iii‐iv. - PubMed
    1. Leinonen M, Nieminen P, Kotaniemi‐Talonen L, et al. Age‐specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst. 2009;101:1612‐1623. - PubMed
    1. Mayrand MH, Duarte‐Franco E, Rodrigues I, et al. Canadian cervical cancer screening trial study G. human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579‐1588. - PubMed
    1. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589‐1597. - PubMed

Publication types

MeSH terms