Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma

The clinical course in urinary bladder cancer is difficult or impossible to predict based on conventional disease parameters. It is a reasonable hypot hesis that the genetic aberrations acquired by the tumor cells, being instr umental in bringing about the disease in the first place, may also hold the key to more reliable prognostication. However, though 200 transitional cel l carcinomas (TCC), the most common bladder cancer in the Western world, wi th clonal chromosomal abnormalities have been reported, our knowledge about the karyotypic characteristics of these tumors remains insufficient. The a berration pattern is clearly nonrandom, but no completely specific primary or secondary karyotypic abnormality has been identified, and the chronologi cal order in which the aberrations appear during disease progression is not well known. The high degree of karyotypic complexity in epithelial tumors like TCC is one reason why our picture of the sequential order of cytogenet ic evolution is unclear. To overcome some of these difficulties we have use d several statistical methods that allow analysis and interpretation of the relationship between cytogenetic aberrations in TCC. We show that there ex ists a temporal order with respect to the appearance of chromosomal imbalan ces and that this order is highly correlated with tumor stage and grade. An alyzing changes in the distribution of imbalances per tumor in G1, G2, and G3 tumors, we suggest that progression involves the acquisition of cytogene tically detectable and submicroscopic genetic changes at comparable frequen cies. By means of computer simulations, we show that the imbalances -9, +7, and 1q+ appear earlier than expected from random events and that -6q, -5q, -18, +5p, -22p, and -15 appear later than expected. Using principal compon ent analysis, we identify two cytogenetic pathways in TCC, one initiated by -9 and followed by -11p and 1q+, the other initiated by +7 and followed by 8p- and +8q. The -9 pathway was correlated with stage Ta-T2 tumors, wherea s the +7 pathway was correlated with stage T1-T3 tumors, i.e., +7 tumors ap peared to be more aggressive. Although these pathways are well separated at earlier stages, they later converge to contain a common set of imbalances.