BOA2
High resolution array Comparative Genomic Hybridization (aCGH) of breast carcinoma identifies Mouse Double Minutes 4 (Mdm4) as one of the early genetic changes in breast cancer development: Mdm4 is a new independent prognostic and predictive marker
Tarek MA Abdel-Fatah1, Des G Powe1, Maryou Lambros3, Jorge S Reis-Filho3, Ian O Ellis1
1University of Nottingham, UK, 2National Liver Institute, Menoufyia University, Menoufyia, Egypt, 3Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
Background
Genome-wide aCGH identified recurrent amplification/gain of chromosome 1:202,752,134-202,862,753 in 86% and 7% of low (LGBC) and high (HGBC) grade breast cancers, respectively. MDM4 gene maps to this locus.
We hypothesised that it may be a candidate oncogene and tested this hypothesis by determining its association with clinical outcome and biological features in BC.
Method
MDM4-mRNA expression levels were assessed in 2 independent sets of gene expression arrays. Protein expression levels were assessed using immunohistochemistry in series of 1081 BCs with long term follow up and series of 140 cases of LGBCs with matched normal terminal ductal lobular units (TDLUs) and precursor lesions including columnar cell lesions, atypical ductal hyperplasia, ductal carcinoma in situ and lobular neoplasia.
Results
MDM4 mRNA expression levels significantly correlated with copy number (Pearson's correlation=0.55, p=0.0001) and this gene is overexpressed when amplified (Mann-Whitney U test p =0.0018). Mdm4 was overexpressed in 17% of BC and was associated with low grade, ER+ and normal expressions of p53, ATM and BRCA1. In cases showing coexistent precursors with invasive component, MDM4 expression was identical in both lesions. On multivariate analysis that included NPI, MDM4-overexpression was an independent prognostic marker for patients survival outcomes [HR, 0.4; p<0.0001]. In high risk patients who had received systemic adjuvant therapy, MDM4-overexpression predicted better response to both hormone- [HR, 2.7; p<0.0001] and chemo-therapies [HR, 6.7; p=0.008].
Conclusion
Mdm4 is an independent prognostic and predictor of BC and its overexpression could represent a novel molecular mechanism by which a subset of BC escapes p53-dependent growth control, providing new avenues for therapeutic intervention.
