DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA
Tang, Q Holland-Letz, T Slynko, A Cuk, K Marme, F Schott, S Heil, J Qu, B Golatta, M Bewerunge-Hudler, M
Tang, Q
Holland-Letz, T
Slynko, A
Cuk, K
Marme, F
Schott, S
Heil, J
Golatta, M
Bewerunge-Hudler, M
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Alternative Title
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.
Keywords
adult, area under the curve, Article, breast cancer, case control study, cell specificity, cohort analysis, controlled study, CpG island, DNA methylation, epigenetics, female, gene, gene locus, genetic association, human, human cell, leukocyte, major clinical study, MGRN1 gene, RAPSN gene, receiver operating characteristic, RPTOR gene, sensitivity and specificity, validation study, aged, blood, breast tumor, comparative study, DNA microarray, gene expression profiling, genetic epigenesis, genetic predisposition, genetics, middle aged, odds ratio, pathology, predictive value, procedures, reproducibility, retrospective study, risk factor, statistical model, circulating tumor DNA, MGRN1 protein, human, muscle protein, peripheral membrane protein 43K, regulatory associated protein of mTOR, RPTOR protein, human, tumor marker, ubiquitin protein ligase, Adult, Aged, Area Under Curve, Biomarkers, Tumor, Breast Neoplasms, Circulating Tumor DNA, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Logistic Models, Middle Aged, Muscle Proteins, Odds Ratio, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Regulatory-Associated Protein of mTOR, Reproducibility of Results, Retrospective Studies, Risk Factors, ROC Curve, Ubiquitin-Protein Ligases
Source Title
Oncotarget
Publisher
Impact Journals LLC
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2016
DOI
10.18632/oncotarget.11640
Type
Article