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Cancer Genes and Genomics

Detecting Cervical Cancer by Quantitative Promoter Hypermethylation Assay on Cervical Scrapings: A Feasibility Study

Departments of ¹ Gynecologic Oncology, ³ Pathology, and ⁴ Epidemiology and Biostatistics, University Hospital Groningen, Groningen, The Netherlands and ² Department of Head and Neck Cancer Research Division, School of Medicine, John Hopkins University, Baltimore, Maryland

Requests for reprints: A.G.J. van der Zee, Department of Gynecologic Oncology, University Hospital Groningen, P.O. Box 30,001, 9700 RB Groningen, The Netherlands. Phone: 31-50-361-3152; Fax: 31-50-361-1806. E-mail: a.g.j.van.der.zee{at}og.azg.nl

Current morphology-based cervical cancer screening is associated with significant false-positive and false-negative results. Tumor suppressor gene hypermethylation is frequently present in cervical cancer. It is unknown whether a cervical scraping reflects the methylation status of the underlying epithelium, and it is therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on cervical scrapings could be used as a future screening method augmenting the current approach. Cervical scrapings and paired fresh frozen cervical tissue samples were obtained from 53 cervical cancer patients and 45 controls. All scrapings were morphologically scored and analyzed with QMSP for the genes APC, DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were calculated against DNA levels of a reference gene. Hypermethylation ratios of paired fresh frozen tissue samples and scrapings of cervical cancer patients and controls were strongly related (Spearman correlation coefficient, 0.80 for APC, 0.98 for DAPK, and 0.83 for MGMT; P < 0.001). More cervical cancer patients than controls were DAPK positive (P < 0.001). When cutoff levels for ratios were defined to be above the highest ratio observed in controls, QMSP in cervical scrapings identified 32 (67%) of 48 cervical cancer patients. This feasibility study demonstrates that QMSP on cervical scrapings holds promise as a new diagnostic tool for cervical cancer. The addition of more genes specifically methylated in cervical cancer will further improve the assay.

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