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Clin Cancer Res. 2017 Jul 15;23(14):3813-3822. doi: 10.1158/1078-0432.CCR-16-2641. Epub 2017 Jan 24.

Genome-wide DNA Methylation Profiling Reveals Methylation Markers Associated with 3q Gain for Detection of Cervical Precancer and Cancer.

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Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
Department of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
Department of Gynecologic Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.


Purpose: Epigenetic host cell changes involved in cervical cancer development following a persistent high-risk human papillomavirus (hrHPV) infection, provide promising markers for the management of hrHPV-positive women. In particular, markers based on DNA methylation of tumor suppressor gene promoters are valuable. These markers ideally identify hrHPV-positive women with precancer (CIN2/3) in need of treatment. Here, we set out to identify biologically relevant methylation markers by genome-wide methylation analysis of both hrHPV-transformed cell lines and cervical tissue specimens.Experimental Design and Results: Genome-wide discovery by next-generation sequencing (NGS) of methyl-binding domain-enriched DNA (MBD-Seq) yielded 20 candidate methylation target genes. Further verification and validation by multiplex-targeted bisulfite NGS and (quantitative) methylation-specific PCR (MSP) resulted in 3 genes (GHSR, SST, and ZIC1) that showed a significant increase in methylation with severity of disease in both tissue specimens and cervical scrapes (P < 0.005). The area under the ROC curve for CIN3 or worse varied between 0.86 and 0.89. Within the group of CIN2/3, methylation levels of all 3 genes increased with duration of lesion existence (P < 0.0005), characterized by duration of preceding hrHPV infection, and were significantly higher in the presence of a 3q gain (P < 0.05) in the corresponding tissue biopsy.Conclusions: By unbiased genome-wide DNA methylation profiling and comprehensive stepwise verification and validation studies using in vitro and patient-derived samples, we identified 3 promising methylation markers (GHSR, SST, and ZIC1) associated with a 3q gain for the detection of cervical (pre)cancer. Clin Cancer Res; 23(14); 3813-22. ©2017 AACR.

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