The development of bladder tumors has been associated with a number of causative agents, including schistosomiasis. Schistosome-related cancers show different clinical and pathological features compared with non-schistosome-related bladder cancers, occurring in younger patients, and being predominantly of squamous cell type. This study addresses the difference between squamous and transitional tumor types in the presence of schistosome infection as a measure of the relationship between tumor genotype and phenotype. We have used comparative genomic hybridization to analyze primary muscleinvasive schistosome-related bladder tumors in 54 patients. Twenty-six of these tumors were squamous cell carcinomas; the remaining 28 were of transitional cell type. On average, transitional cell tumors showed 1.8 times the number of chromosomal aberrations as squamous cell tumors (14.4 versus 8.2, P: < 0.001). For both groups combined, the most prevalent genetic alterations were losses of 8p and 18q, and gains of 8q. Transitional cell cancers also showed frequent losses involving 5q, 9p, 10q, 11p and 11q, and gains at 1q and 17q. Loss of 11p was significantly more frequent in TCC than in SCC tumors (50 versus 4%, P: = 0.01). Squamous cell cancers showed more frequent losses of 17p and 18p than transitional tumors, which was clearly significant given the overall reduced frequency of changes in squamous cancers (P: = 0.001 and P: = 0.03, respectively). These data show that different histologic subgroups of bladder tumors are characterized by distinct patterns of chromosomal alterations. The genetic changes found in the transitional cell group are similar to those reported in non-schistosome-related transitional cell tumors, but differ from tumors exhibiting squamous differentiation.
SUMMARY:Deletion of chromosome 8p is associated with the progression of bladder cancer. To identify the putative tumor suppressor gene locus we have analyzed 145 bladder cancers with 12 microsatellite markers for allelic changes at the chromosome 8p23.3 region. We mapped the smallest overlapping deletion to approximately 0.7 cM genetic distance between loci D8S504 and D8S264. Allelic changes at this region occurred in 75 (52%) of the 145 tumors. We found a significant correlation between alterations at chromosome 8p23.3 and the tumor grade. The correlation between genetic changes and tumor stage reflected the distribution of tumors of different grades in each pathologic stage. (Lab Invest 2000, 80:1089-1093. P revious DNA studies detected allelic changes at several chromosomal regions in transitional cell carcinomas (TCC) of the urinary bladder (Knowles, 1999). Because loss of heterozygosity (LOH) at chromosome 9p occurs in 80% to 90% of TCC, it is believed to be an initial genetic event (Baud et al, 1998;Orlow et al, 1994;Stadler et al, 1994). Alteration of the chromosome 8p region was shown in 22% to 54% of bladder TCC in RFLP, microsatellite, and comparative genomic hybridization (CGH) studies (Hovey et al, 1998;Kallioniemi et al, 1995;Knowles et al, 1993;Ohgaki et al, 1999;Richter et al, 1997Richter et al, , 1998Richter et al, , 1999Simon et al, 1998;Takle and Knowles, 1996). When genetic changes and tumor stages were evaluated, loss of chromosome 8p sequences showed an association with invasive growth of TCC. Fluorescence in situ hybridization (FISH) analysis by using bacterial artificial chromosome (BAC) clones found a correlation between loss of signal at the chromosome 8p22 band and tumor progression (Wagner et al, 1997). Recently, the putative tumor suppressor gene was mapped to an approximately 1 Mb region on chromosome 8p22 (Ohgaki et al, 1999). Other studies showed deletion of the entire chromosome 8p or large regions encompassing several chromosomal bands in TCC.In a pilot study, we performed deletion mapping of 56 bladder cancers with 14 microsatellite markers covering the entire chromosome 8p. We delineated an approximately 4 cM region of LOH between loci D8S264 and D8S262 on chromosome 8p23.3 (unpublished data). Allelic changes at this region were associated with grade and stage of TCC. Deletion mapping studies on other types of cancer have also suggested that this chromosomal region may harbor a tumor suppressor gene (Ishwad et al, 1999;Perinchery et al, 1999;Pineau et al, 1999;Scholnick et al, 1996;Wright et al, 1998;Wu et al, 1997). To delineate the putative tumor suppressor gene locus, we analyzed 145 bladder cancers for 12 microsatellite loci at chromosome 8p23.3. We defined a smallest overlapping region of approximately 0.7 cM genetic distance between loci D8S504 and D8S264 and we found a correlation between LOH and tumor grade. Results Defining the Tumor Gene Locus at Chromosome 8p23.3Microsatellite loci and their position are shown in Figure 1. We detected LOH at all informative loci at c...
A doxorubicin-resistant human bladder carcinoma cell line RT112/D21 was established by continuous exposure of the parental line RT112 to increasing concentrations of doxorubicin over a period of 9 months. RT112/D21 cells expressed significantly more P-170 glycoprotein than the parental line, and rhodamine 123 efflux, as a functional parameter of P-170 glycoprotein activity, was increased. RT112/D21 cells were 96 times more resistant to doxorubicin than RT112 cells, and cross-resistance to epirubicin and vinblastine was present. Sensitivity to methotrexate and mitomycin C remained unchanged. R-verapamil reversed resistance to doxorubicin, epirubicin and vinblastine in RT112/D21 cells but did not affect sensitivity to methotrexate and mitomycin C. In RT112 cells, R-verapamil had no effect on drug sensitivity. Thus, it may be assumed that primary or induced MDR1 gene-encoded P-170 glycoprotein expression is a relevant mechanism of chemoresistance in transitional cell carcinoma, and that chemotherapeutic strategies in combination with chemosensitizers improve response rates.
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