Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance

• Published in: Cancers Vol. 13; no. 13; p. 3309
• Main Authors: Hoyer, Heike, Mehlhorn, Grit, Scheungraber, Cornelia, Hagemann, Ingke, Hirchenhain, Christine, Woelber, Linn, Stolte, Claudia, Hampl, Monika, Scherbring, Sarah, Denecke, Agnieszka, Bartels, Janina, Ebert, Andreas D., Meneder, Sabina, Petzold, Annett, Heller, Tabitha, Heidtke, Karsten R., Schwarz, Elisabeth, Stübs, Frederik, Schütze, Stefanie, Stange, Eva-Lena, Jaeger, Anna, Martignoni, Franca, Dellmann, Ansgar, Rody, Achim, Hillemanns, Peter, Fehm, Tanja, Petry, Karl-Ulrich, Böhmer, Gerd, Schmalfeldt, Barbara, Wimberger, Pauline, Beckmann, Matthias W., Runnebaum, Ingo B., Dürst, Matthias
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.07.2021; MDPI
• Subjects: Biomarkers; Carcinogenesis; Cellular biology; Cervical cancer; Cervical carcinoma; Cervix; Cytology; Deoxyribonucleic acid; DNA; DNA methylation; DNA sequencing; Genomes; Gynecology; Human papillomavirus; Integration; Laboratories; Medical screening; Patients; Polymerase chain reaction; Sensitivity analysis; Surgery; Surveillance; Womens health; Germany
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13133309

Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients’ individual HPV-integration sites (vcj-PCR on the basis of NGS). Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6–34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8–27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7–20.7%) and predicted ten of fourteen recurrences at six months. Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.