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Clin Cancer Res. 2018 Jul 15;24(14):3456-3464. doi: 10.1158/1078-0432.CCR-17-3615. Epub 2018 Apr 9.

Identification and Validation of a 3-Gene Methylation Classifier for HPV-Based Cervical Screening on Self-Samples.

Author information

1
Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
2
Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands.
3
Department of Gynecology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, the Netherlands.
4
Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands.
5
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
6
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
7
Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands. r.steenbergen@vumc.nl.

Abstract

Purpose: Offering self-sampling of cervico-vaginal material for high-risk human papillomavirus (hrHPV) testing is an effective method to increase the coverage in cervical screening programs. Molecular triage directly on hrHPV-positive self-samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a DNA methylation classifier for detection of cervical precancer (CIN3) and cancer, applicable to lavage and brush self-samples.Experimental Design: We determined genome-wide DNA methylation profiles of 72 hrHPV-positive self-samples, using the Infinium Methylation 450K Array. The selected DNA methylation markers were evaluated by multiplex quantitative methylation-specific PCR (qMSP) in both hrHPV-positive lavage (n = 245) and brush (n = 246) self-samples from screening cohorts. Subsequently, logistic regression analysis was performed to build a DNA methylation classifier for CIN3 detection applicable to self-samples of both devices. For validation, an independent set of hrHPV-positive lavage (n = 199) and brush (n = 287) self-samples was analyzed.Results: Genome-wide DNA methylation profiling revealed 12 DNA methylation markers for CIN3 detection. Multiplex qMSP analysis of these markers in large series of lavage and brush self-samples yielded a 3-gene methylation classifier (ASCL1, LHX8, and ST6GALNAC5). This classifier showed a very good clinical performance for CIN3 detection in both lavage (AUC = 0.88; sensitivity = 74%; specificity = 79%) and brush (AUC = 0.90; sensitivity = 88%; specificity = 81%) self-samples in the validation set. Importantly, all self-samples from women with cervical cancer scored DNA methylation-positive.Conclusions: By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on hrHPV-positive self-samples, which is superior to currently available methods. Clin Cancer Res; 24(14); 3456-64. ©2018 AACR.

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