TY - JOUR
T1 - HPV and DNA Methylation Testing in Urine for Cervical Intraepithelial Neoplasia and Cervical Cancer Detection
AU - van den Helder, Rianne
AU - Steenbergen, Renske D. M.
AU - van Splunter, Annina P.
AU - Mom, Constantijne H.
AU - Tjiong, Ming Y.
AU - Martin, Ivonne
AU - Rosier-van Dunné, Fleur M. F.
AU - van der Avoort, Irene A. M.
AU - Bleeker, Maaike C. G.
AU - van Trommel, Nienke E.
N1 - Funding Information: R. van den Helder reports grants from Hanarth Foundation and grants from Stichting Weijerhorst during the conduct of the study. R.D.M. Steenbergen reports other support from Self-screen B.V. outside the submitted work; in addition, R.D.M. Steenbergen has a patent for methylation markers for cervical cancer detection pending to Self-screen B.V. N.E. van Trommel reports grants from Hanarth Foundation during the conduct of the study. No disclosures were reported by the other authors. Funding Information: This research was funded by the Hanarth Foundation and Weijerhorst Foundation. The funders had no role in the design of the study; in the collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Publisher Copyright: © 2022 American Association for Cancer Research
PY - 2022/5/15
Y1 - 2022/5/15
N2 - Purpose: Biomarker detection in urine offers a potential solution to increase effectiveness of cervical cancer screening programs by attracting nonresponders. In this prospective study, the presence of high-risk human papillomavirus (hrHPV) DNA and the performance of DNA methylation analysis was determined for the detection of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN2/3) in urine, and compared with paired cervicovaginal self-samples and clinician-taken cervical scrapes. Experimental Design: A total of 587 samples were included from 113 women with cervical cancer, 92 women with CIN2/3, and 64 controls. Samples were tested for hrHPV DNA and five methylation markers. Univariate and multivariate logistic regression and leave-one-out cross-validation were used to determine the methylation marker performance for CIN3 and cervical cancer (CIN3þ) detection in urine. Agreement between samples was determined using Cohen kappa statistics and the Spearman correlation coefficients. Results: HrHPV presence was high in all sample types, 79% to 92%. Methylation levels of all markers in urine significantly increased with increasing severity of disease. The optimal marker panel (ASCL1/LHX8) resulted in an AUC of 0.84 for CIN3þ detection in urine, corresponding to an 86% sensitivity at a 70% predefined specificity. At this threshold 96% (109/113) of cervical cancers, 68% (46/64) of CIN3, and 58% (14/24) of CIN2 were detected. Between paired samples, a strong agreement for HPV16/18 genotyping and a fair to strong correlation for methylation was found. Conclusions: HrHPV DNA and DNA methylation testing in urine offers a promising solution to detect cervical cancer and CIN2/3 lesions, especially for women currently unreached by conventional screening methods.
AB - Purpose: Biomarker detection in urine offers a potential solution to increase effectiveness of cervical cancer screening programs by attracting nonresponders. In this prospective study, the presence of high-risk human papillomavirus (hrHPV) DNA and the performance of DNA methylation analysis was determined for the detection of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN2/3) in urine, and compared with paired cervicovaginal self-samples and clinician-taken cervical scrapes. Experimental Design: A total of 587 samples were included from 113 women with cervical cancer, 92 women with CIN2/3, and 64 controls. Samples were tested for hrHPV DNA and five methylation markers. Univariate and multivariate logistic regression and leave-one-out cross-validation were used to determine the methylation marker performance for CIN3 and cervical cancer (CIN3þ) detection in urine. Agreement between samples was determined using Cohen kappa statistics and the Spearman correlation coefficients. Results: HrHPV presence was high in all sample types, 79% to 92%. Methylation levels of all markers in urine significantly increased with increasing severity of disease. The optimal marker panel (ASCL1/LHX8) resulted in an AUC of 0.84 for CIN3þ detection in urine, corresponding to an 86% sensitivity at a 70% predefined specificity. At this threshold 96% (109/113) of cervical cancers, 68% (46/64) of CIN3, and 58% (14/24) of CIN2 were detected. Between paired samples, a strong agreement for HPV16/18 genotyping and a fair to strong correlation for methylation was found. Conclusions: HrHPV DNA and DNA methylation testing in urine offers a promising solution to detect cervical cancer and CIN2/3 lesions, especially for women currently unreached by conventional screening methods.
UR - http://www.scopus.com/inward/record.url?scp=85130634011&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-21-3710
DO - https://doi.org/10.1158/1078-0432.CCR-21-3710
M3 - Article
C2 - 35266975
SN - 1078-0432
VL - 28
SP - 2061
EP - 2068
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -