Use of High Resolution Array Comparative Genomic Hybridization (aCGH) To Identify Mouse Double Minutes 4 (Mdm4) as an
Early Genetic Change in Breast Cancer Development: Evaluation of Mdm4 as a New Prognostic and Predictive Marker
TMA Abdel-Fatah, DG Powe, M Lambros, R Natrajan, A Green, JS Reis-Filho, IO
Ellis. School of Molecular Medical Sciences and Nottingham University Hospitals Trust, University of Nottingham, Nottingham, United Kingdom; Institute of Cancer Research, London, United Kingdom.
Background: aCGH identified recurrent gain of chromosome 1q31-32 in >50% of BC. MDM4 gene maps to this locus. We hypothesised that it may be a candidate oncogene and tested this hypothesis on several levels: 1) Copy number alteration, 2) mRNA expression, 3) protein expression and 4) clinicopathological outcome.
Design: aCGH was performed for three independent BC series. MDM4-mRNA expression levels were assessed in 2-independent sets of gene expression arrays. Protein expression levels were assessed using immunohistochemistry in two-series of 1081 BCs with long term follow up and 140 cases of BC with matching normal terminal ductal lobular units (TDLUs) and precursor lesions.
Results: Amplification of MDM4 was detected in 15% and 8% of low and high grade BC; respectively. 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 ER+ patients absence of MDM4- overexpression predicted better response to hormone therapy [HR, 2.7; p<0.0001].
Conclusions: 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.
Use of High Resolution Array Comparative Genomic Hybridization (aCGH) To Identify Mouse Double Minutes 4 (Mdm4) as an
Early Genetic Change in Breast Cancer Development: Evaluation of Mdm4 as a New Prognostic and Predictive Marker
TMA Abdel-Fatah, DG Powe, M Lambros, R Natrajan, A Green, JS Reis-Filho, IO
Ellis. School of Molecular Medical Sciences and Nottingham University Hospitals Trust, University of Nottingham, Nottingham, United Kingdom; Institute of Cancer Research, London, United Kingdom.
Background: aCGH identified recurrent gain of chromosome 1q31-32 in >50% of BC. MDM4 gene maps to this locus. We hypothesised that it may be a candidate oncogene and tested this hypothesis on several levels: 1) Copy number alteration, 2) mRNA expression, 3) protein expression and 4) clinicopathological outcome.
Design: aCGH was performed for three independent BC series. MDM4-mRNA expression levels were assessed in 2-independent sets of gene expression arrays. Protein expression levels were assessed using immunohistochemistry in two-series of 1081 BCs with long term follow up and 140 cases of BC with matching normal terminal ductal lobular units (TDLUs) and precursor lesions.
Results: Amplification of MDM4 was detected in 15% and 8% of low and high grade BC; respectively. 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 ER+ patients absence of MDM4- overexpression predicted better response to hormone therapy [HR, 2.7; p<0.0001].
Conclusions: 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.
