Genome-wide study of gene copy numbers, transcripts, and protein levels in pairs of non-invasive and invasive human transitional cell carcinomas.

Gain and loss of chromosomal material is characteristic of bladder cancer, as well as malignant transformation in general. The consequences of these changes at both the transcription and translation levels is at present unknown partly because of technical limitations. Here we have attempted to address this question in pairs of non-invasive and invasive human bladder tumors using a combination of technology that included comparative genomic hybridization, high density oligonucleotide array-based monitoring of transcript levels (5600 genes), and high resolution two-dimensional gel electrophoresis. The results showed that there is a gene dosage effect that in some cases superimposes on other regulatory mechanisms. This effect depended (p < 0.015) on the magnitude of the comparative genomic hybridization change. In general (18 of 23 cases), chromosomal areas with more than 2-fold gain of DNA showed a corresponding increase in mRNA transcripts. Areas with loss of DNA, on the other hand, showed either reduced or unaltered transcript levels. Because most proteins resolved by two-dimensional gels are unknown it was only possible to compare mRNA and protein alterations in relatively few cases of well focused abundant proteins. With few exceptions we found a good correlation (p < 0.005) between transcript alterations and protein levels. The implications, as well as limitations, of the approach are discussed.