Research Papers:

Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma

Rong Wang, Robert W. van Leeuwen, Aniek Boers, Harry G. Klip, Tim de Meyer, Renske D. M. Steenbergen, Wim van Criekinge, Ate G. J. van der Zee, Ed Schuuring and G. Bea A. Wisman _

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Oncotarget. 2016; 7:80735-80750. https://doi.org/10.18632/oncotarget.12598

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Rong Wang1,3,*, Robert W. van Leeuwen1,*, Aniek Boers1, Harry G. Klip1, Tim de Meyer4, Renske D. M. Steenbergen5, Wim van Criekinge4, Ate G. J. van der Zee1, Ed Schuuring2, G. Bea A. Wisman1

1Department of Gynecologic Oncology, University of Groningen, University Medical Centre Groningen, Cancer Research Centre Groningen, Groningen, The Netherlands

2Department of Pathology, University of Groningen, University Medical Centre Groningen, Cancer Research Centre Groningen, Groningen, The Netherlands

3Department of Laboratory Medicine, Tianjin Medical University, Tianjin, China

4Department of Mathematical Modeling, Statistics and Bio-informatics, University of Ghent, Ghent, Belgium

5Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Ed Schuuring, email: [email protected]

G. Bea A. Wisman, email: [email protected]

Keywords: uterine cervical neoplasms, DNA methylation biomarkers, MethylCap-seq, adenocarcinoma (in situ), (quantitative) methylation-specific PCR ((Q)MSP)

Received: July 14, 2016     Accepted: September 29, 2016     Published: October 12, 2016


Background: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC.

Results: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10-5).

Conclusion: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.

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