A34
Identification of a biomarker of DNA repair deficiency via expression profiling of BRCA1 and BRCA2 deficient human tumours and cell-lines using a breast specific platform
Jude Mulligan1, Fionnuala McDyer1, Vadim Farztdinov1, Thomas Delaney1, Iris Halfpenny1, Fergus Couch2, Jennifer Quinn3, Paul Harkin1, Peter Kerr1, Richard Kennedy1
1Almac Diagnostics, Craigavon, UK, 2Mayo Clinic, Rochester, USA, 3Queen's University, Belfast, UK
There is increased focus within breast cancer research, on identification of reliable biomarkers to aid in accurate classification of the disease, predicting its progression and patients response to both available therapies and those in development. DNA microarrays are a powerful tool for global analysis of gene transcript expression and they have in recent years become one of the key elements of biological research. We have characterised the transcriptome of breast cancer and used this information to create a unique disease focused microarray that is designed to work with formalin fixed paraffin embedded (FFPE) tissue.
Gene expression profiling was carried out on a number of ERα-positive and ERα-negative cell-line models in which BRCA1 and BRCA2 was silenced using siRNA technology. A cohort of BRCA1 and BRCA2 mutant tumours and matched wild-type controls were also profiled. The differentially expressed genes from the cell-lines were used for comparison with, and functional enrichment of, the gene expression profiles of the tumour samples. We found that the differentially expressed genes common to both the cell-line and tumour data were primarily concerned with cell-cycle control and DNA-damage response. Unsupervised analysis using this list of common genes identified a subset of sporadic tumour samples that were classified amongst the BRCA1 and BRCA2 mutant tumours. Further analysis of the genes characteristic of these sporadic tumours and the BRCA1 mutant tumours show a strong correlation in abrogation of DNA response pathways in both cohorts. This would suggest that the sporadic tumours are defective in DNA-repair response, and are therefore candidates for targeted therapy such as PARP-1 inhibitors.
