title: Assessment of gene promoter hypermethylation for detection of cervical neoplasia.
abstract: Current cervical cancer screening is based on morphological assessment of Pap smears and associated with significant false negative and false positive results. Previously, we have shown that detection of hypermethylated genes in cervical scrapings using quantitative methylation-specific PCR (QMSP) is a promising tool for identification of squamous cell cervical cancer. Aim of the present pilot-study was to evaluate presence of hypermethylated genes in cervical carcinogenesis, both in squamous cell as well as adenocarcinomas. Cervical scrapings were obtained from 30 patients diagnosed with cervical cancer (20 squamous cell carcinomas and 10 adenocarcinomas) and 19 women with histologically normal cervices. The scraped cells were used for determination of promoter hypermethylation by QMSP for 12 genes and for morphological assessment. Overall, CALCA, DAPK, ESR1, TIMP3, APC and RAR-beta2 promoters were significantly more often hypermethylated in cancers than in controls, while adenocarcinomas were more often hypermethylated above the highest control ratio for APC, TIMP3 and RASSF1A promoters. Combining 4 genes (CALCA, DAPK, ESR1 and APC) yielded a sensitivity of 89% (with all adenocarcinomas identified), equal to cytomorphology (89%) and high-risk human papilloma virus (Hr-HPV; 90%). The 4-gene QMSP proved theoretically superior to cytomorphology as well as Hr-HPV in specificity (100% vs. 83 and 68%, respectively), because cytology identified 3 controls as moderate or severe dyskaryosis and 6 controls were positive for Hr-HPV. In conclusions, QMSP of 4 gene promoters combined appears to have comparable sensitivity and potentially better specificity in comparison to "classic" cytomorphological assessment and Hr-HPV detection. QMSP holds promise as a new diagnostic tool for both squamous cell carcinoma and adenocarcinoma of the cervix.
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, The Netherlands. g.b.a.wisman@og.umcg.nl
authors.forename: G Bea A
authors.initials: GB
authors.lastname: Wisman
authors.forename: Esther R
authors.initials: ER
authors.lastname: Nijhuis
authors.forename: Mohammad O
authors.initials: MO
authors.lastname: Hoque
authors.forename: Nathalie
authors.initials: N
authors.lastname: Reesink-Peters
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Koning
authors.forename: Haukeline H
authors.initials: HH
authors.lastname: Volders
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Buikema
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Ed
authors.initials: E
authors.lastname: Schuuring
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
mesh_terms: D019175:DNA Methylation; D005260:Female; D006801:Humans; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000821:virology