title: TMEM45A, SERPINB5 and p16INK4A transcript levels are predictive for development of high-grade cervical lesions.
abstract: Women persistently infected with human papillomavirus (HPV) type 16 are at high risk for development of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+). We aimed to identify biomarkers for progression to CIN3+ in women with persistent HPV16 infection. In this prospective study, 11,088 women aged 20-29 years were enrolled during 1991-1993, and re-invited for a second visit two years later. Cervical cytology samples obtained at both visits were tested for HPV DNA by Hybrid Capture 2 (HC2), and HC2-positive samples were genotyped by INNO-LiPA. The cohort was followed for up to 19 years via a national pathology register. To identify markers for progression to CIN3+, we performed microarray analysis on RNA extracted from cervical swabs of 30 women with persistent HPV16-infection and 11 HPV-negative women. Six genes were selected and validated by quantitative PCR. Three genes were subsequently validated within a different and large group of women from the same cohort. Secondly, Kaplan-Meier and Cox-regression analyses were used to investigate whether expression levels of those three genes predict progression to CIN3+. We found that high transcript levels of TMEM45A, SERPINB5 and p16INK4a at baseline were associated with increased risk of CIN3+ during follow-up. The hazard ratios of CIN3+ per 10-fold increase in baseline expression level were 1.6 (95% CI: 1.1-2.3) for TMEM45A, 1.6 (95% CI: 1.1-2.5) for p16INK4a, and 1.8 (95% CI: 1.2-2.7) for SERPINB5. In conclusion, high mRNA expression levels of TMEM45A, SERPINB5 and p16INK4a were associated with increased risk of CIN3+ in persistently HPV16-infected women.
authors: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen Elfriede-Aulhorn Str. 6, 72076 Tübingen, Germany.
authors: Anna
authors: A
authors: Manawapat-Klopfer
authors: Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors: Louise T
authors: LT
authors: Thomsen
authors: Institute for Clinical Epidemiology and Applied Biometry Silcherstraße 5, 72076 Tübingen, Germany.
authors: Peter
authors: P
authors: Martus
authors: Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors: Christian
authors: C
authors: Munk
authors: Genedata AG Margarethenstrasse 38, CH-4053 Basel, Switzerland.
authors: Rainer
authors: R
authors: Russ
authors: Genedata AG Margarethenstrasse 38, CH-4053 Basel, Switzerland.
authors: Hans
authors: H
authors: Gmuender
authors: Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors: Kirsten
authors: K
authors: Frederiksen
authors: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen Elfriede-Aulhorn Str. 6, 72076 Tübingen, Germany.
authors: Juliane
authors: J
authors: Haedicke-Jarboui
authors: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen Elfriede-Aulhorn Str. 6, 72076 Tübingen, Germany.
authors: Frank
authors: F
authors: Stubenrauch
authors: Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research CenterStrandboulevarden 49, DK-2100 Copenhagen, Denmark; Department of Obstetrics and Gynecology, Rigshospitalet, University of CopenhagenBlegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors: Susanne K
authors: SK
authors: Kjaer
authors: Division of Experimental Virology, Institute of Medical Virology, University Hospital Tübingen Elfriede-Aulhorn Str. 6, 72076 Tübingen, Germany.
authors: Thomas
authors: T
authors: Iftner
keywords: CIN3+; Cervical cancer; HPV16; SERPINB5; TMEM45A; biomarker; p16INK4A