Research Papers:
DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA
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Abstract
Qiuqiong Tang1,2, Tim Holland-Letz3, Alla Slynko3, Katarina Cuk1,2, Frederik Marme1, Sarah Schott1, Jörg Heil4, Bin Qu5, Michael Golatta4, Melanie Bewerunge-Hudler6, Christian Sutter7, Harald Surowy1,2, Barbara Wappenschmidt8, Rita Schmutzler8, Markus Hoth5, Peter Bugert9, Claus R. Bartram7, Christof Sohn1, Andreas Schneeweiss1,10, Rongxi Yang1,2, Barbara Burwinkel1,2
1Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
2Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
3Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg, Germany
4Department of Gynecology and Obstetrics, University Women’s Clinic, Heidelberg, Germany
5Department of Biophysics, Center for Integrated Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg (Saar), Germany
6Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
7Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
8Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany
9Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, German Red Cross Blood Service Baden, Württemberg, Hessen, Mannheim, Germany
10National Centre for Tumor Diseases, Heidelberg, Germany
Correspondence to:
Qiuqiong Tang, email: [email protected]
Rongxi Yang, email: [email protected]
Barbara Burwinkel, email: [email protected]
Keywords: breast cancer, DNA methylation, MGRN1, RAPSN, RPTOR
Received: May 30, 2016 Accepted: August 13, 2016 Published: August 26, 2016
ABSTRACT
DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.
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