IDENTIFYING EPIGENETIC CHANGES IN BREAST TUMOURS THAT METASTASISE TO THE BRAIN


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Rajendra P Pangeni1, David Huen1, Katherine Ashton2, Carol Walker3, Timothy P Dawson2, Charles H G Davis2, Farida Latif4, John L Darling1, Tracy J Warr1, Mark R Morris1
1Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK,2Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK,3The Walton Centre NHS Foundation Trust, Liverpool, UK,4Department of Medical and Molecular Genetics, University of Birmingham, Birmingham, UK

Abstract

Background

Following what appears to be a successful treatment of breast cancer, tumours can recur. Many of these secondary, metastatic cancers develop in the brain, and this is fatal.

Method

Genome-wide methylation analysis by 450K arrays was carried out on 20 brain metastases that originated as breast tumours. Combined Bisulphite Restriction Analysis (COBRA), Methylation-specific PCR (MSP) and Q-PCR confirmed candidate metastatic-specific alterations.

 

Results

Following genome-wide methylation analysis (by methylation-specific arrays) we have identified nine genes, that are epigenetically dysregulated in breast to brain metastases. Using robust laboratory techniques we have confirmed that all these genes are dysregulated in the metastatic tumour. Moreover, some of these genes carry erroneous promoter methylation in the originating primary breast tumours but not in tumours with no evidence of metastasis.

We have also show that these metastasis-specific marks can be identified in tumour-associated DNA isolated from patient blood.

It is of interest that half of the genes identified here encode non-translated RNAs and are associated with many different cellular processes, including regulation of gene expression and control of RNA stability.

Conclusion

We hope that the identification of these genes may lead to the development of prognostic biomarkers that could be used to predict the risk of brain metastases from breast tumours and provide important molecular information relating to the existing metastatic tumour. These genes may also provide novel therapeutic targets.

 

 

 

Background

Most breast cancer-related deaths are caused by metastasis and 18-30% of patients with breast cancer eventually develop brain metastases. There is little in the way of prognostic markers for breast-to-brain metastasis. It is unclear which genomic alterations found in primary breast cancer contribute to metastasis to specific secondary sites such as the brain. We hypothesize that many of the alterations that drive metastasis will be epigenetic in nature.

Method

To identify epigenetic drivers of brain metastasis we have carried out Genome-wide methylation analysis of 24 metastatic brain tumours that originated from primary breast tumours. These data were compared to previously published methylation data for primary breast tumours and normal breast tissues.

Results

We identified 49 genes that were differentially methylated in metastatic brain tumours compared to normal tissues and primary breast tumours. Seven of these genes were hypermethylated and 22 were hypomethylated in metastatic brain tumours compared to primary breast tumours.  The genes identified are associated with a wide variety cellular processes including gene expression control of RNA stability.

Conclusion

The DNA methylation and associated genes identified in this study suggest that there are specific epigenetic alterations associated with cells that metastases to the brain; these could be used as therapeutic targets or prognostic markers.