Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer

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 nonoverlapping 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.