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Updated: Jul 5, 2026
Magnetic Resonance Imaging Assessment of Carcinogen-induced Murine Bladder Tumors
Published on: March 29, 2019
High-resolution array-based comparative genomic hybridization of bladder cancers identifies mouse double minute 4
Abhi Veerakumarasivam1, Helen E Scott, Suet-Feung Chin
1Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Purpose:
Loss of p53 function in urothelial cell carcinoma (UCC) by mutation or inactivation disrupts normal cell cycle checkpoints, generating a favorable milieu for genomic instability, a hallmark of UCC. The aim of this study was to characterize novel DNA copy number changes to identify putative therapeutic targets.
Experimental Design:
We report our findings using array comparative genomic hybridization on a whole-genome BAC/PAC/cosmid array with a median clone interval of 0.97 Mb to study a series of UCC cases. TP53 status was determined by direct sequencing, and an in-house tissue microarray was constructed to identify protein expression of target genes.
Results:
Array comparative genomic hybridization allowed identification of novel regions of copy number changes in addition to those already known from previous studies. A novel amplification previously unreported in UCC was identified at 1q32. A chromosome 1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade. Copy number changes of MDM4 and MDM2 occurred exclusively in tumors with wild-type p53. Overexpression of MDM4 corresponded to disruption of p53 transcriptional activity. Immunohistochemistry on an independent series by tissue microarray identified an inverse relationship between Mdm4 and Mdm2, with Mdm4 expression highest in invasive UCC.
Conclusion:
The data indicate that gain/amplification and overexpression of MDM4 is a novel molecular mechanism by which a subset of UCC escapes p53-dependent growth control, thus providing new avenues for therapeutic intervention.
Insights
Loss of p53 function in urothelial cell carcinoma (UCC) leads to genomic instability. This study identified mouse double minute 4 (MDM4) amplification as a novel mechanism for UCC to evade p53 control, offering new therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Loss of p53 function in urothelial cell carcinoma (UCC) promotes genomic instability.
- Identifying novel DNA copy number alterations is crucial for discovering therapeutic targets in UCC.
Purpose of the Study:
- To characterize novel DNA copy number changes in UCC.
- To identify potential therapeutic targets by understanding molecular mechanisms of UCC progression.
Main Methods:
- Utilized array comparative genomic hybridization (aCGH) on a whole-genome BAC/PAC/cosmid array to analyze UCC cases.
- Determined TP53 status via direct sequencing and assessed protein expression using an in-house tissue microarray.
- Employed a chromosome 1 tile path array to pinpoint amplified genes in tumors with gains.
Main Results:
- Identified novel copy number changes in UCC, including a previously unreported amplification at 1q32.
- Pinpointed mouse double minute 4 (MDM4) homologue as the amplified gene at 1q32, with its mRNA expression correlating with copy number and tumor grade.
- Observed MDM4 and MDM2 copy number changes exclusively in wild-type p53 tumors, and MDM4 overexpression correlated with disrupted p53 activity.
Conclusions:
- Gain/amplification and overexpression of MDM4 represent a novel mechanism for UCC to escape p53-dependent growth control.
- These findings suggest MDM4 as a potential therapeutic target for a subset of UCC patients.
- The study provides new avenues for therapeutic intervention in urothelial cell carcinoma.
