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.
Highlights
Breast cancer is the most frequent cancer among women worldwide
Our analysis showed a significant difference between primary tumor and paired normal breast samples for all 22 CpGs (Additional file 1: Table S1)
In this study, we evaluated the potential use of DFNA5 methylation and expression as detection and prognostic biomarker in breast cancer, on basis of data obtained from The Cancer Genome Atlas (TCGA)
Summary
Breast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. 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. Breast cancer is the most frequent cancer among women, with nearly 1.67 million new cases diagnosed in 2012 [1] It is a heterogeneous disease consisting of two main histological subtypes, ductal and lobular adenocarcinomas, that differ with respect to clinical presentation, morphological and molecular features, and clinical behavior [2,3,4,5]. We hypothesize that DFNA5 may be a valuable epigenetic biomarker, based upon large differences in DFNA5 methylation between breast cancer and healthy breast tissues, strong indications for its role as tumor suppressor gene, and its function in regulated cell death
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