TY - JOUR
T1 - Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women
T2 - A large European multicenter study
AU - Bonde, Jesper
AU - Floore, Arno
AU - Ejegod, Ditte
AU - Vink, Frederique J
AU - Hesselink, Albertus
AU - van de Ven, Peter M
AU - Oštrbenk Valenčak, Anja
AU - Pedersen, Helle
AU - Doorn, Saskia
AU - Quint, Wim G
AU - Petry, K Ulrich
AU - Poljak, Mario
AU - Stanczuk, Grazyna
AU - Cuschieri, Kate
AU - de Sanjosé, Silvia
AU - Bleeker, Maaike
AU - Berkhof, Johannes
AU - Meijer, Chris J L M
AU - Heideman, Daniëlle A M
N1 - Funding Information: The project was funded by the SME Instrument of the European Commission in the HORIZON2020 (Valid‐screen contract ID: 666800). Funding Information: This work is dedicated to our colleague Prof. Dr. P.J.F. Snijders, who passed away on May 27, 2018 and Prof. Dr. Karl Ulrich Petry, who passed away April 21st, 2020. We thank the following for technical assistance: Jana Mlakar, Snje?ana Frkovi? Grazio, Maja Primic ?akelj, Ur?ka Ivanu? (Slovenia), Ali Hamdi Said al-Fatal (Denmark), and Prof. Renske Steenbergen, and the technicians at the molecular pathology unit. Publisher Copyright: © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - In HPV cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicentre, 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 two 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. This article is protected by copyright. All rights reserved.
AB - In HPV cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID-SCREEN is a EU-multicentre, 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 two 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. This article is protected by copyright. All rights reserved.
KW - DNA hypermethylation
KW - biomarker
KW - cervical carcinoma
KW - cervical screening
KW - human genome methylation
KW - human papillomavirus
UR - http://www.scopus.com/inward/record.url?scp=85092905660&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.33320
DO - https://doi.org/10.1002/ijc.33320
M3 - Article
C2 - 32997803
SN - 0020-7136
VL - 148
SP - 396
EP - 405
JO - International journal of cancer
JF - International journal of cancer
IS - 2
ER -