Oncotarget

Research Papers:

c-myc copy number gain is a powerful prognosticator of disease outcome in cervical dysplasia

Kirsten Kübler _, Sally Heinenberg, Christian Rudlowski, Mignon-Denise Keyver-Paik, Alina Abramian, Sabine Merkelbach-Bruse, Reinhard Büttner, Walther Kuhn and Hans-Ulrich Schildhaus

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Oncotarget. 2015; 6:825-835. https://doi.org/10.18632/oncotarget.2706

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Abstract

Kirsten Kübler1,*, Sally Heinenberg1,*, Christian Rudlowski1,2, Mignon-Denise Keyver-Paik1, Alina Abramian1, Sabine Merkelbach-Bruse3,4, Reinhard Büttner3,4, Walther Kuhn1, Hans-Ulrich Schildhaus3,4,5

1Department of Obstetrics and Gynecology, Center for Integrated Oncology, University of Bonn, 53127 Bonn, Germany

2Evangelisches Krankenhaus, Teaching Hospital of the University of Bonn, 51465 Bergisch Gladbach, Germany

3Institute of Pathology, Center for Integrated Oncology, University of Bonn, 53127 Bonn, Germany

4Institute of Pathology, Center for Integrated Oncology, University of Cologne, 50937 Cologne, Germany

5Institute of Pathology, University of Göttingen, 37075 Göttingen, Germany

* These authors have contributed equally to this work

Correspondence to:

Kirsten Kübler, e-mail: Kirsten.Kuebler@ukb.uni-bonn.de

Keywords: cervical intraepithelial neoplasia, FISH analysis, copy number gain, prognostic signature, c-myc

Received: November 05, 2014     Accepted: November 08, 2014     Published: December 16, 2014

ABSTRACT

Cervical carcinoma develops from preneoplasia by a multistep process. Although most low-grade dysplastic lesions will regress without intervention and even high-grade changes exhibit a substantial rate of regression, a small percentage of dysplasia will progress over time. Thus, indicators are needed to estimate the biological risk and to help avoid overtreatment in women who desire to preserve fertility. In addition to the classical biomarkers, PCR-ELISA-determined HPV genotype and immunohistochemically assessed p16INK4a and Ki-67 expression, cells with integrated HPV and copy number gain of TERC and c-myc were quantified in a panel of 104 benign, intraepithelial neoplastic (CIN I, II, III) and cancerous lesions using fluorescence in situ hybridization. Optimal cut-off values were calculated; Kaplan-Meier curves and a Cox proportional hazard regression model were used to evaluate prognostic signatures. The assay reliably identified HPV integration, TERC and c-myc copy number gain as determined by comparisons with established biomarkers. All biomarker levels increased with the progression of the disease. However, only c-myc copy number gain independently prognosticated a low probability of dysplastic regression. Our results suggest that c-myc plays a key role in the process of dysplastic transformation and might thus be exploited for treatment and follow-up decision-making of cervical dysplasia.


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