Molecular progression and clonality or urinary bladder cancer

Abstract: The general aim of this work was to investigate the clonality of multifocal bladder tumours, chromosomal deletions and model the initiation-progression of bladder tumours at a molecular level using microsatellite analysis. In a population-based study, we found correlation between stage and grade and the prevalence of loss of heterozygosity (LOH) at all observed chromosome 13 loci and stage and grade, respectively. Statistically significant correlation was found for 13q14.3, the Rb locus, and between the number of loci with LOH at 13q and tumour stage and grade, respectively. Clonality was studied using superficial multifocal bladder tumours. The given patient had always lost the same microsatellite allele when LOH was encompassed, suggesting monoclonality of the tumours. In the majority of the cases the polyclonality was excluded with at least 1-2x10-16 probability, calculated using binomial distribution. At chromosome 9, at least three consensus regions were found to be deleted at superficial multifocal bladder tumours, one at 9p (9p21-22) and two at 9q (9q21-22 and 9q32-34). All the regions appeared to be equally important and during the development of tumours all these regions were finally affected. At chromosome 3 at three loci on chromosome 3p25-26, 3p14.2 and 3q27 had frequent LOH in multifocal superficial bladder tumours. The phylogenetic-type analysis suggested that the FHIT region at 3p14.2 contain often the very first alterations at chromosome 3. The tumour-adjacent surrounding tissues were found to contain similar alterations as the tumour tissues. On chromosome 9 all the patients analysed showed LOH in at least one surrounding sample and over 60% of them showed LOH also on chromosome 3. On chromosome 9 three distinct clusters of LOH were found, 9p21-22, 9q13-22 and 9q31-34.2 and at chromosome 3p (D3S3050) and at 3q27 (D3S2418).