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Int. J. Mol. Sci. 2017, 18(10), 2032; doi:10.3390/ijms18102032

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

1
Department of Gynecology, Jena University Hospital—Friedrich Schiller University Jena, 07747 Jena, Germany
2
Institute of Medical Statistics, Information Sciences and Documentation, Jena University Hospital—Friedrich Schiller University Jena, 07743 Jena, Germany
3
Research Program Infection and Cancer, DKFZ, 69120 Heidelberg, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 31 July 2017 / Revised: 6 September 2017 / Accepted: 14 September 2017 / Published: 22 September 2017
(This article belongs to the Special Issue Human Polyomaviruses and Papillomaviruses)
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Abstract

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. View Full-Text
Keywords: HPV; viral-cellular junction; molecular marker; tumor heterogeneity; cell-free tumor DNA HPV; viral-cellular junction; molecular marker; tumor heterogeneity; cell-free tumor DNA
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Carow, K.; Gölitz, M.; Wolf, M.; Häfner, N.; Jansen, L.; Hoyer, H.; Schwarz, E.; Runnebaum, I.B.; Dürst, M. Viral-Cellular DNA Junctions as Molecular Markers for Assessing Intra-Tumor Heterogeneity in Cervical Cancer and for the Detection of Circulating Tumor DNA. Int. J. Mol. Sci. 2017, 18, 2032.

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