Novel DNA methylation markers were identified, of which cg12374721 ( PRAC2), cg18081940 ( TDRD10) and cg04475027 ( TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.īreast cancer (BC) is a highly heterogeneous disease, comprising multiple histological and molecular subtypes that are associated with distinct clinical behaviours and therapeutic responses. We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue.
Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). A subset of genes that had not previously been studied in cancer was chosen for further analysis. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. Gene expression changes were subsequently validated in the METABRIC dataset. Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA).
The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses.
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