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

• Published in: Oncotarget 2016-12, Vol.7 (49), p.80735-80750
• Main Authors: Wang, Rong, van Leeuwen, Robert W, Boers, Aniek, Klip, Harry G, de Meyer, Tim, Steenbergen, Renske D M, van Criekinge, Wim, van der Zee, Ate G J, Schuuring, Ed, Wisman, G Bea A
• Format: Article
• Language: English
• Subjects: Adenocarcinoma in Situ - genetics; Adenocarcinoma in Situ - pathology; Adult; Aged; Biomarkers, Tumor - genetics; Carcinoma, Adenosquamous - genetics; Carcinoma, Adenosquamous - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Case-Control Studies; Cervical Intraepithelial Neoplasia - genetics; Cervical Intraepithelial Neoplasia - pathology; DNA Methylation; Early Detection of Cancer; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Glycine Plasma Membrane Transport Proteins - genetics; Humans; Middle Aged; Phenotype; Predictive Value of Tests; Prognosis; Reproducibility of Results; Research Paper; SOXB1 Transcription Factors - genetics; SOXB2 Transcription Factors - genetics; T-Box Domain Proteins - genetics; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Vaginal Smears
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12598

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