Viral-Cellular DNA Junctions as Molecular Markers for Assessing Intra-Tumor Heterogeneity in Cervical Cancer and for the Detection of Circulating Tumor DNA

GND
1169709702
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Carow, Katrin;
GND
1303291339
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Gölitz, Mandy;
GND
1303293749
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University
Wolf, Maria;
GND
136906303
ORCID
0000-0002-7012-483X
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Häfner, Norman;
GND
1247758273
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Jansen, Lars;
GND
1241138044
Zugehörigkeit
Institute of Medical Statistics, Information Sciences and Documentation, Jena University Hospital—Friedrich Schiller University Jena
Hoyer, Heike;
Zugehörigkeit
Research Program Infection and Cancer, DKFZ, 69120 Heidelberg, Germany,
Schwarz, Elisabeth;
GND
1111567727
ORCID
0000-0002-6702-4651
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Runnebaum, Ingo;
GND
1111821518
ORCID
0000-0003-1235-1150
Zugehörigkeit
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena
Dürst, Matthias

The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV) DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA) junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s) were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring.

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