Dataset Information

DFNA5 promoter methylation a marker for breast tumorigenesis.

ABSTRACT:

Background

Identification of methylation markers that are sensitive and specific for breast cancer may improve early detection. We hypothesize that DFNA5 promoter methylation can be a valuable epigenetic biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death.

Results

Statistically different levels of methylation were seen, with always very low levels in healthy breast reduction samples, very high levels in part of the adenocarcinoma samples and slightly increased levels in part of the normal tissue samples adjacent the tumor. One of the CpGs (CpG4) showed the best differentiation. A ROC curve for DFNA5 CpG4 methylation showed a sensitivity of 61.8% for the detection of breast cancer with a specificity of 100%.

Materials and methods

We performed methylation analysis on four CpGs in the DFNA5 promoter region by bisulfite pyrosequencing on 123 primary breast adenocarcinomas and 24 healthy breast reductions. For 16 primary tumors, corresponding histological normal tissue adjacent to the tumor was available.

Conclusions

We conclude that DFNA5 methylation shows strong potential as a biomarker for detection of breast cancer. Slightly increased methylation in histologically normal breast tissue surrounding the tumor suggests that it may be a good early detection marker.

SUBMITTER: Croes L

PROVIDER: S-EPMC5458261 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

DFNA5 promoter methylation a marker for breast tumorigenesis.

Croes Lieselot L de Beeck Ken Op KO Pauwels Patrick P Vanden Berghe Wim W Peeters Marc M Fransen Erik E Van Camp Guy G

Oncotarget 20170501 19

<h4>Background</h4>Identification of methylation markers that are sensitive and specific for breast cancer may improve early detection. We hypothesize that DFNA5 promoter methylation can be a valuable epigenetic biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death.<h4>Results</h4>Statistically different levels of methylation were seen, with always very low levels in healthy breast reduction samples, very high levels in part of th ...[more]

PMID: 28404884

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Project description:Background:Breast 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). Results:DFNA5 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. Conclusions:We conclude that DFNA5 methylation shows strong potential as detection and prognostic biomarker for breast cancer.

Project description:BackgroundInhibitor of DNA binding/Inhibitor of differentiation 4 (ID4) is a critical factor for cell proliferation and differentiation in normal vertebrate development. ID4 has regulative functions for differentiation and growth of the developing brain. The role of ID1, ID2 and ID3 are expected to be oncogenic due to their overexpression in pancreatic cancer and colorectal adenocarcinomas, respectively. Aside from these findings, loss of ID3 expression was demonstrated in ovarian cancer. The aim of the present study was to reveal the factual role of ID4 in carcinogenesis in more detail, since its role for the pathogenesis of human breast cancer has been discussed controversially, assigning both oncogenic and tumour suppressive functions.MethodsID4 promoter methylation, ID4 mRNA expression and ID4 protein expression were analysed in primary human breast cancer specimens using methylation-specific PCR (MSP) (n=170), semiquantitative realtime RT-PCR (n=46) and immunhistochemistry (n=3), respectively. In order to demonstrate a functional association of ID4 promoter methylation with its gene silencing, we performed DNA demethylation analysis with four human breast cell lines using MSP and semiquantitative realtime RT-PCR. In addition, we performed correlations of ID4 promoter methylation with ID4 mRNA and ID4 protein expression in matched samples of breast tumour and corresponding normal tissue. We carried out statistical analyses in order to find correlations between ID4 promoter methylation and clinicopathological parameters.ResultsFrequent ID4 promoter methylation was observed in primary breast cancer samples (69%, 117/170). We found a tight correlation (P<0.0001) between ID4 promoter methylation and loss of ID4 expression in primary breast cancer 3 specimens. Demethylating treatment with breast cancer cell lines was associated with clear ID4 mRNA re-expression. Tumours with ID4 promoter methylation showed distinct loss of ID4 expression on both transcription and protein level. Interestingly, ID4 promoter methylation was a factor for unfavourable recurrence-free survival (P=0.036) and increased risk for lymph node metastasis (P=0.030).ConclusionID4 is indeed a novel tumour suppressor gene in normal human breast tissue and is epigenetically silenced during cancer development, indicating increased risk for tumour relapse. Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer.

Dataset Information

DFNA5 promoter methylation a marker for breast tumorigenesis.

Background

Results

Materials and methods

Conclusions

Publications

DFNA5 promoter methylation a marker for breast tumorigenesis.

Similar Datasets

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