Clinical Research Papers:

GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers

Evgeny A. Moskalev _, Pouria Jandaghi, Mahdi Fallah, Mehdi Manoochehri, Sandeep K. Botla, Oleg V. Kolychev, Evgeny A. Nikitin, Vladymyr V. Bubnov, M. von Knebel Doeberitz, Oliver Strobel, Thilo Hackert, Markus W. Büchler, Nathalia Giese, Andrea Bauer, Thomas Muley, Arne Warth, Peter Schirmacher, Florian Haller, Jörg D. Hoheisel and Yasser Riazalhosseini

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Oncotarget. 2015; 6:4418-4427. https://doi.org/10.18632/oncotarget.2759

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Evgeny A. Moskalev1,10,*, Pouria Jandaghi1,*, Mahdi Fallah2, Mehdi Manoochehri1, Sandeep K. Botla1, Oleg V. Kolychev3, Evgeny A. Nikitin4, Vladymyr V. Bubnov5, M. von Knebel Doeberitz6, Oliver Strobel7, Thilo Hackert7, Markus W. Büchler7, Nathalia Giese7, Andrea Bauer1, Thomas Muley8,11, Arne Warth9, Peter Schirmacher9, Florian Haller10, Jörg D. Hoheisel1, Yasser Riazalhosseini1,12

1Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany

2Molecular Genetic Epidemiology, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany

3Military Training Research Center, Zhukovsky – Gagarin Air Force Academy, 394064 Voronezh, Russia

4Molecular Haematology, National Research Centre for Haematology, 125167 Moscow, Russia

5Department of Genomics and Immunology, Odessa State Medical University, 265026 Odessa, Ukraine

6Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany

7Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany

8Translational Research Unit, Thoraxklinik Heidelberg at Heidelberg University, Heidelberg, Germany

9Institute of Pathology, University Hospital, 69120 Heidelberg, Germany

10Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany

11Department of Translational Pneumology, Translational Lung Research Centre Heidelberg (TLRC-H), Member of the German Centre for Lung Research (DZL), 69120 Heidelberg, Germany

12Current address: Department of Human Genetics and McGill University and Genome Quebec Innovation Centre, H3A 0G1 Montreal, Quebec

*These authors have contributed equally to this work

Correspondence to:

Yasser Riazalhosseini, e-mail: [email protected]

Keywords: DNA methylation, Cancer, Diagnosis, GHSR, Epigenetics

Received: September 24, 2014     Accepted: November 16, 2014     Published: December 30, 2014


Identification of a single molecular trait that is determinant of common malignancies may serve as a powerful diagnostic supplement to cancer type-specific markers. Here, we report a DNA methylation mark that is characteristic of seven studied malignancies, namely cancers of lung, breast, prostate, pancreas, colorectum, glioblastoma and B cell chronic lymphocytic leukaemia (CLL) (n = 137). This mark was defined by substantial hypermethylation at the promoter and first exon of growth hormone secretagouge receptor (GHSR) through bisulfite pyrosequencing. The degree of aberrant methylation was capable of accurate discrimination between cancer and control samples. The highest sensitivity and specificity of cancer detection was achieved for cancers of pancreas, lung, breast and CLL yielding the area under the curve (AUC) values of 1.0000, 0.9952, 0.9800 and 0.9400, respectively. Narrowing to a single CpG site within the gene’s promoter or four consecutive CpG units of the highest methylation levels within the first exon improved the detection power. GHSR hypermethylation was detected already at the early stage tumors. The accurate performance of this marker was further replicated in an independent set of pancreatic cancer and control samples (n = 78). These findings support the candidature of GHSR methylation as a highly accurate pan-cancer marker.

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