Allelic Imbalances in Human Bladder Cancer: Genome-Wide Detection With High-Density Single-Nucleotide Polymorphism Arrays

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Abstract
Background: Bladder cancer is characterized by genomic instability. In this study, we investigated whether genome-wide screening using single-nucleotide polymorphism (SNP) arrays could detect allelic imbalance (loss or gain of at least one allele) in bladder cancers. Methods: For microarray analysis, DNA was isolated from microdissected bladder tumors and leukocytes from 11 patients. The stage T1 tumor (connective tissue invasive) and the subsequent stage T2–4 tumor (muscle invasive) were available from eight of these patients, and only the first muscle-invasive stage T2–4 tumor was available from three of the 11 patients. The microarray contained 1494 biallelic polymorphic sequences. For microsatellite analyses, DNA was isolated from tumors and leukocytes of nine patients with primary T2–4 tumors and 13 patients with Ta (noninvasive) tumors. All statistical tests were two-sided. Results: We assigned a genotype to 1204 loci, 343 of which were heterozygous. Allelic imbalance was detected in known areas of imbalance on chromosomes 6, 8, 9, 11, and 17, and a new area of imbalance was detected on the p arm of chromosome 6. Microsatellite analysis of nine other T2–4 tumors and 13 Ta tumors showed that allelic imbalance was more frequent in T2–4 tumors than in Ta tumors (P<.001). We detected 8.5 allelic imbalances (median) in 348 informative loci in T1 tumors and 28 allelic imbalances (median) in 329 informative loci in T2–4 tumors. When pairs of T1 and T2–4 tumors were analyzed from eight patients, 68% of imbalances detected in T1 tumors (146 imbalances) occurred in the subsequent T2–4 tumors (99 imbalances). Homozygous TP53 mutations were more often associated (P = .005) with high allelic imbalance than with low allelic imbalance. Conclusion: SNP arrays are feasible for high-throughput, genome-wide scanning for allelic imbalances in bladder cancer.

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