Identifying epigenetic changes in breast tumours that metastasise to the brain
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.
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.
This analysis identified genes that are differentially methylated in primary breast tumours and secondary brain tumours. These genes are either i) infrequently methylated in normal tissues and primary breast tumours while frequently methylated in metastatic brain tumours or ii) frequently methylated in normal tissues and primary tumours while infrequently methylated in metastatic brain tumours. Differential methylation was validated by Combined Bisulphite and Restriction Analysis (CoBRA) in metastatic brain tumours and their associated originating primary breast tumours from individual patients (matched pairs). Associated gene expression was also assessed.
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.
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.
We would like to gratefully acknowledge Theo Giannopoulos and Susanne Booth at Castle Hill Hospital for their help in acquiring ovarian tissue samples, and Jane Smales for coordinating the clinical aspects of the study. This study is funded by a grant from NC3Rs (Registry File: G1100600).
References to go here