Molecular evolution of multiple recurrent cancers of the bladder

We describe the reconstruction of bladder tumor development in individual p atients spanning periods of up to 17 years. Genomic alterations detected in the tumors were used for hierarchical cluster analysis of tumor subclones. The cluster analysis highlights the clonal relationship between tumors fro m each patient. Based on the cluster date we were able to reconstruct the e volution of tumors in a genetic tree, where tumors with few aberrations pre cede those with many genetic insults. The sequential order of the tumors in these pedigrees differs from the chronological order in which the tumors a ppear. Thus, a tumor with few alterations can be occult for years following removal of a more deranged derivative. Extensive genetic damage is seen to accumulate during the evolution of the tumors. To explain the type and ext ent of genetic damage in combination with the low stage and grade of these tumors, we hypothesize that in bladder cancer pathogenesis an increased rat e of mitotic recombination is acquired early in the tumorigenic process.