ORIGINS AND CLINICAL IMPLICATIONS OF ANEUPLOIDY IN EARLY BLADDER-CANCER

Cytogenetic and flow cytometric studies in a variety of human solid tu mors have suggested that gross aneuploidy may arise by a process of ab rupt chromosome complement doubling followed by gradual chromosome las s, However, this sequence has not been demonstrated directly in serial studies in individual patients in vivo, The purpose of this study was to search for evidence of chromosome complement doubling and subseque nt chromosome loss in flow cytometric ploidy patterns in serial bladde r washings and/or biopsies from individual patients with early bladder cancer, Fifty-two patients with noninvasive bladder cancer were follo wed with serial flow cytometric DNA studies for periods ranging from 5 .1 to 42.7 months (median 15.1 months), Serial changes in DNA ploidy a nd S phase fractions were recorded and correlated with histologic and/ or cytologic findings, response to treatment and clinical outcome, The data suggest a series of genetic evolutionary changes in early bladde r cancer that include the initial development of peridiploid aneuploid y and repeated rounds of DNA content doubling with chromosome loss in patients with progressive disease, It is likely that gross DNA aneuplo idy, and more specifically, DNA multiploidy and DNA hypertetraploidy, all arise by this mechanism, The sequence of DNA diploidy, peridiploid aneuploidy, near-tetraploidy, hypotetraploidy and hypertetraploidy is associated with a progressive increase in S phase fraction, and with increasing tumor grade; late steps in this ploidy sequence were often present in tumors that were refractory to local therapeutic measures a nd tumors that developed deep tumor invasion and/or distant metastases , We conclude that DNA multiploidy and hypertetraploidy are markers of advanced stages of genetic evolution in human bladder cancer. (C) 199 5 Wiley-Liss, Inc.