LOSS OF HETEROZYGOSITY ON CHROMOSOME-9 AND LOSS OF CHROMOSOME-9 COPY NUMBER ARE SEPARATE EVENTS IN THE PATHOGENESIS OF TRANSITIONAL-CELL CARCINOMA OF THE BLADDER

The most frequent genetic aberration found in transitional cell carcin oma (TCC) of the bladder involves chromosome 9. Loss of heterozygosity (LOH) analyses show deletions of both chromosome 9p and 9q, while in situ hybridization studies suggest a significant percentage of tumours with monosomy 9. To investigate the types of chromosome 9 losses that occur in bladder cancer, we have studied 40 tumours with different te chniques such as in site hybridization (ISH), flow cytometry and LOH a nalysis. LOH for one or more markers was found in 43% of the tumours, This percentage does not differ from previous reports, With ISH, compl ete monosomy for chromosome 9 was observed in only 1 of the 40 tumours . Four other tumours had monosomic subpopulations, representing 23- 40 % of the cells. In 18 cases, an underrepresentation of the chromosome 9 centromere relative to chromosome 6 or to the ploidy of the tumour w as observed, including the cases with monosomy. In 5 of these 18 cases , the relative loss could not be confirmed by LOH. In addition, when L OH and a relative underrepresentation were observed in the same tumour , the extent of LOH as measured by the intensity of allele loss, was o ften not related to the extent of underrepresentation. We therefore co nclude that complete monosomy of chromosome 9 is rave in TCCs of the b ladder and that a relative loss of centromere signal may not be relate d to a loss compatible with inactivation of a tumour suppressor gene, LOH was found in TCCs of all stages and grades. Our results suggest th at loss of tumour suppressor genes on chromosome 9 is an early event i n the pathogenesis of bladder cancer. (C) 1998 Wiley-Liss, Inc.