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Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer
Ronald Simon1, Kirsten Struckmann, Peter Schraml
1Institute for Pathology and Urologic Clinics, University of Basel, Schoenbeinstrasse 40, CH-4003 Basel, Switzerland.
Abstract:
The chromosomal region 12q13-q15 is recurrently amplified in bladder cancer. Putative target genes located in this region include MDM2, CDK4, and GLI. To evaluate the involvement of these genes in bladder cancer, we screened a tissue microarray (TMA) containing 2317 samples by fluorescence in situ hybridization (FISH). Amplification was found for MDM2 in 5.1%, for CDK4 in 1.1%, and for GLI in 0.4% of interpretable tumors. Among tumors having amplification of at least one of these 12q13-q15 genes, 76.6% had amplification of MDM2 alone and 6.4% had amplification of CDK4 alone. Coamplifications were seen of MDM2 and CDK4 in 10.6%, and of CDK4 and GLI in 6.4%. Neither coamplifications of all three genes nor isolated GLI amplifications were found. These data suggest a prominent role of MDM2 as a 12q13-q15 amplification target in bladder cancer. However, independent CDK4 amplifications do also occur suggesting either two non-overlapping amplification sites or else a minimal overlapping region between MDM2 and CDK4 perhaps containing another yet unknown oncogene. The frequency of amplification increased significantly from stage pTa to pT1-4 (P<0.04) and from low to high grade (P<0.005). These data are consistent with a high level of genetic instability in invasively growing and high-grade bladder tumors.
Insights
MDM2 amplification is prominent in bladder cancer, with CDK4 also amplified independently. Amplification frequency correlates with advanced stage and high grade, indicating genetic instability in invasive tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The 12q13-q15 chromosomal region is frequently amplified in bladder cancer.
- Key genes in this region include MDM2, CDK4, and GLI, which are potential oncogenes.
Purpose of the Study:
- To investigate the amplification status and clinical significance of MDM2, CDK4, and GLI in a large cohort of bladder cancer tissues.
- To determine the frequency and patterns of coamplification among these target genes.
Main Methods:
- Utilized fluorescence in situ hybridization (FISH) on a tissue microarray (TMA) comprising 2317 bladder cancer samples.
- Analyzed amplification frequencies for MDM2, CDK4, and GLI, as well as their coamplification patterns.
Main Results:
- Amplification of MDM2, CDK4, and GLI was observed in 5.1%, 1.1%, and 0.4% of tumors, respectively.
- MDM2 amplification was most common, often occurring alone (76.6% of amplified cases). Coamplifications of MDM2 and CDK4 were noted in 10.6% of cases.
- Amplification frequency significantly increased with tumor stage (pTa to pT1-4) and grade (low to high), suggesting a link to tumor progression and genetic instability.
Conclusions:
- MDM2 is a primary target of 12q13-q15 amplification in bladder cancer.
- Independent CDK4 amplifications suggest distinct or partially overlapping amplification events.
- The observed correlation between gene amplification and advanced stage/grade supports the role of genetic instability in aggressive bladder tumors.