Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer

Abstract

BackgroundBreast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. We hypothesized that deafness, autosomal dominant 5 (DFNA5) may be a valuable biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death. In this study, we aimed to analyze DFNA5 methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of DFNA5 as detection and/or prognostic marker in breast cancer. We analyzed Infinium HumanMethylation450k data, covering 22 different CpGs in the DFNA5 gene (668 breast adenocarcinomas and 85 normal breast samples) and DFNA5 expression (Agilent 244K Custom Gene Expression: 476 breast adenocarcinomas and 56 normal breast samples; RNA-sequencing: 666 breast adenocarcinomas and 71 normal breast samples).ResultsDFNA5 methylation and expression were significantly different between breast cancer and normal breast samples. Overall, breast cancer samples showed higher DFNA5 methylation in the putative gene promoter compared to normal breast samples, whereas in the gene body and upstream of the putative gene promoter, the opposite is true. Furthermore, DFNA5 methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5, which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93). This model was externally validated in three independent datasets. Moreover, we showed that estrogen receptor state is associated with DFNA5 methylation and expression. Finally, we were able to find a significant effect of DFNA5 gene body methylation on a 5-year overall survival time.ConclusionsWe conclude that DFNA5 methylation shows strong potential as detection and prognostic biomarker for breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0479-y) contains supplementary material, which is available to authorized users.

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

“…Recently, the role of GSDME in the pathogenesis of human malignancies has attracted increasing attention. Due to promoter hypermethylation, GSDME is inactivated in several cancers (24)(25)(26). Our previous studies demonstrated that chemotherapy, including 5-FU and lobaplatin, could induce pyroptosis in gastrointestinal cancer by cleaving GSDME (27,28).…”

A five-DNA methylation signature act as a novel prognostic biomarker in patients with ovarian serous cystadenocarcinoma

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“…The expression analysis of these ten genes between high- and low-risk patients indicated that one possible reason was that mRNAs acting as biomarkers had larger fold changes in the expression level to be captured by our statistical methods. Further, it is generally believed that DNA methylation has an effect on the gene regulation with several exceptions [ 6 , 39 ]. The potential association between the methylation level and the gene expression levels of these five genes demonstrated that only the expression of SLC39A14 and CORO6 was significantly ( P < 0.05) correlated with the methylation levels at cg05254747 and cg06038133 sites, respectively, and no statistically significant association was observed between the methylation level and the expression of the other three genes.…”

“…DNA methylation is well known to be associated with ovarian cancer and has great potential to serve as a biomarker in screening the disease, monitoring response to therapy, and predicting the prognosis [ 5 , 6 ]. The methylation of particular subsets of CpG islands may have consequences for specific processes of tumorigenesis [ 7 ].…”

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