DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood |
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Authors: | Katrin Pfütze Manuela Zucknick Christian Sutter Barbara Wappenschmidt Frederik Marme Bin Qu Katarina Cuk Christoph Engel Sarah Schott Andreas Schneeweiss Hermann Brenner Rainer Claus Christoph Plass Peter Bugert Markus Hoth Christof Sohn Rita Schmutzler Claus R Bartram Barbara Burwinkel |
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Institution: | 1. Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany;2. Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany;3. Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany;4. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany;5. Department of Gynecology and Obstetrics, Clinical Center of University of Cologne, Cologne, Germany;6. Department of Biophysics, Saarland University, Homburg (Saar), Germany;7. Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany;8. Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Heidelberg, Germany;9. Division of Epigenomics and Cancer Risk Factors (C010), German Cancer Research Center (DKFZ), Heidelberg, Germany;10. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service Baden‐Württemberg – Hessen, Mannheim, Germany |
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Abstract: | Breast cancer (BC) is the leading cause of cancer‐related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC‐associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome‐wide methylation screening and identified a BC‐associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p = 2.61 × 10?9 adjusted for cell‐type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650‐bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p‐value of 0.006. To note, the BC‐associated decreased HYAL2 methylation was replicated in the T‐cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early‐stage BC cases (stages 0 and I) from healthy controls area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC = 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood‐based marker for the detection of early BC. |
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Keywords: | HYAL2 methylation breast cancer early detection marker |
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