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

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 t...

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Published inCancers 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
LanguageEnglish
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
Online AccessGet full text
ISSN2072-6694
2072-6694
DOI10.3390/cancers13133309

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Abstract 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.
AbstractList 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.PURPOSEPost-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.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).METHODSPre-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).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.RESULTSIntegration 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.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.CONCLUSIONSAlthough 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.
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.
Simple SummaryHPV-DNA integration into the host genome is a frequent step in cervical carcinogenesis and is considered to be a tumor-driving event. Viral integration sites are unique for each patient and could thus serve as highly specific molecular markers for the detection of recurrent disease. Unexpectedly, our study showed that integration sites as individualized biomarkers could not detect all recurrent pre-cancers (CIN2/3). Nevertheless, this is the first study which has identified and validated integration sites in a large number of CIN3 (n = 445) and as such has unraveled several novel findings: The integration frequency observed in CIN3 was much lower than anticipated (10.8% in CIN3 vs. 80% in cervical cancer). Moreover, in contrast to the monoclonal situation in cervical carcinoma, integrated HPV-DNA in CIN3 is most likely confined to clonally expanding subpopulations.AbstractPurpose: 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.
Author Jaeger, Anna
Wimberger, Pauline
Petzold, Annett
Hillemanns, Peter
Fehm, Tanja
Runnebaum, Ingo B.
Ebert, Andreas D.
Hampl, Monika
Stübs, Frederik
Hirchenhain, Christine
Meneder, Sabina
Mehlhorn, Grit
Scherbring, Sarah
Bartels, Janina
Rody, Achim
Schütze, Stefanie
Scheungraber, Cornelia
Heidtke, Karsten R.
Dellmann, Ansgar
Beckmann, Matthias W.
Stange, Eva-Lena
Böhmer, Gerd
Schwarz, Elisabeth
Woelber, Linn
Hagemann, Ingke
Martignoni, Franca
Heller, Tabitha
Schmalfeldt, Barbara
Petry, Karl-Ulrich
Hoyer, Heike
Dürst, Matthias
Stolte, Claudia
Denecke, Agnieszka
AuthorAffiliation 16 Deutsches Krebsforschungszentrum, ATV, 69120 Heidelberg, Germany; elisabeth.schwarz@alumni.dkfz.de
2 Frauenklinik, Universitätsklinikum Erlangen, 91054 Erlangen, Germany; grit.mehlhorn@uk-erlangen.de (G.M.); frederik.stuebs@uk-erlangen.de (F.S.); fk-direktion@uk-erlangen.de (M.W.B.)
3 Klinik und Poliklinik für Frauenheilkunde und Fortpflanzungsmedizin, Universitätsklinikum Jena, 07747 Jena, Germany; scheungraber@outlook.com (C.S.); annett.petzold@med.uni-jena.de (A.P.); stefanie.schuetze@med.uni-jena.de (S.S.); ingo.runnebaum@med.uni-jena.de (I.B.R.)
17 Städtisches Klinikum Braunschweig gGmbH, 38118 Braunschweig, Germany; a.dellmann@klinikum-braunschweig.de
5 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Technische Universität Dresden, 01307 Dresden, Germany; christine.hirchenhain@uniklinikum-dresden.de (C.H.); pauline.wimberger@uniklinikum-dresden.de (P.W.)
14 Zentrum für Klinische Studien (ZKS), Universitätsklinikum Jena, 07747 Jena, Germany; tabitha.heller@med.uni-jena.d
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– name: 11 Klinik für Frauenheilkunde und Geburtshilfe, Medizinische Hochschule Hannover (MHH), 30625 Hannover, Germany; bartels@kinderwunsch-hildesheim.de (J.B.); hillemanns.peter@mh-hannover.de (P.H.)
– name: 10 Klinikum Wolfsburg, 38440 Wolfsburg, Germany; agnieszka.denecke@klinikum.wolfsburg.de (A.D.); gyn@klinikum.wolfsburg.de (K.-U.P.)
– name: 12 Praxis für Gynäkologie und Geburtshilfe, Ärztehaus Nürnberger Str. 67, 10787 Berlin, Germany; info@prof-ebert.de
– name: 8 Frauenklinik, Universitätsklinikum Düsseldorf, 40225 Düsseldorf, Germany; hampl@med.uni-duesseldorf.de (M.H.); frauenarzt-westend@medicover.de (F.M.); tanja.fehm@med.uni-duesseldorf.de (T.F.)
– name: 3 Klinik und Poliklinik für Frauenheilkunde und Fortpflanzungsmedizin, Universitätsklinikum Jena, 07747 Jena, Germany; scheungraber@outlook.com (C.S.); annett.petzold@med.uni-jena.de (A.P.); stefanie.schuetze@med.uni-jena.de (S.S.); ingo.runnebaum@med.uni-jena.de (I.B.R.)
– name: 15 ATLAS Biolabs GmbH, Aroser Allee 68, 13407 Berlin, Germany; heidtke@atlas-biolabs.com
– name: 4 abts+partner Partnerschaftsgesellschaft, Prüner Gang 7, 24103 Kiel, Germany; i.hagemann@abts-partner.de (I.H.); eva-lena.stange@posteo.de (E.-L.S.)
– name: 14 Zentrum für Klinische Studien (ZKS), Universitätsklinikum Jena, 07747 Jena, Germany; tabitha.heller@med.uni-jena.de
– name: 16 Deutsches Krebsforschungszentrum, ATV, 69120 Heidelberg, Germany; elisabeth.schwarz@alumni.dkfz.de
– name: 1 Institut für Medizinische Statistik, Informatik und Datenwissenschaften, Universitätsklinikum Jena, 07743 Jena, Germany; heike.hoyer@med.uni-jena.de
– name: 7 Institut für Zytologie und Dysplasie (IZD), Theaterstr. 14, 30159 Hannover, Germany; stolte@izd-hannover.de (C.S.); boehmer@izd-hannover.de (G.B.)
– name: 9 Fachärzte für Frauenheilkunde und Geburtshilfe, Karrenführerstraße 1-3, 38100 Braunschweig, Germany; info@gyn-braunschweig.de
– name: 2 Frauenklinik, Universitätsklinikum Erlangen, 91054 Erlangen, Germany; grit.mehlhorn@uk-erlangen.de (G.M.); frederik.stuebs@uk-erlangen.de (F.S.); fk-direktion@uk-erlangen.de (M.W.B.)
– name: 17 Städtisches Klinikum Braunschweig gGmbH, 38118 Braunschweig, Germany; a.dellmann@klinikum-braunschweig.de
– name: 13 Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Schleswig-Holstein (UKSH), 23538 Lübeck, Germany; sabina.meneder@uksh.de (S.M.); achim.rody@uksh.de (A.R.)
– name: 6 Klinik für Gynäkologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany; lwoelber@uke.de (L.W.); a.jaeger@uke.de (A.J.); b.schmalfeldt@uke.de (B.S.)
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2021 by the authors. 2021
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Present affiliation: Praxis für Frauenheilkunde und Geburtshilfe, Westbahnhofstr. 2, 07745 Jena, Germany.
Passed away 20 April 2020.
Present affiliation: Frauenarztpraxis, Neustädter Kirchenplatz 1a, 91054 Erlangen, Germany.
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0000-0001-9829-3531
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Snippet 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...
Simple SummaryHPV-DNA integration into the host genome is a frequent step in cervical carcinogenesis and is considered to be a tumor-driving event. Viral...
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...
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SubjectTerms 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
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Title Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance
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