A. Hartmann et al., Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis, LAB INV, 80(5), 2000, pp. 709-718
Multifocality and recurrence are clinically important features of urothelia
l carcinomas of the urinary bladder. Recent molecular genetic studies have
suggested that multifocal urothelial carcinomas are monoclonally derived fr
om an identical transformed progenitor cell. However, most of these studies
investigated advanced and poorly differentiated tumors. The study presente
d focuses on early papillary tumors, including 52 superficial well-differen
tiated multifocal and recurrent bladder carcinomas from 10 patients. Microd
issection separating urothelium from stromal cells was considered essential
to obtain pure tumor cell populations. Genetic analysis was carried out by
applying two different methods. Dual color fluorescence in situ hybridizat
ion (FISH) with centromeric probes for chromosomes 9 and 17 and gene-specif
ic probes for chromosome loci 9q22, 9p21, and 17p13 was carried out in para
llel to loss of heterozygosity (LOH) analyses applying 5 microsatellite mar
kers on these chromosomes. Overall, deletions on chromosome 9p were found i
n 47 tumors (90%), at chromosome 9q in 36 tumors (69%) and at chromosome 17
p in 3 tumors (6%). There was a very high correlation of the results betwee
n FISH and LOH analysis. Ten early superficial papillary tumors showed dele
tion of chromosome 9p without deletion of 9q, suggesting 9p deletions as a
very early event in the development of papillary urothelial carcinoma. Alth
ough in four patients, all investigated tumors showed identical genetic alt
erations and one patient showed no genetic alterations at the loci investig
ated, in five patients, two or more clones with different deletions were fo
und. In four of these patients, the results are compatible with clonal dive
rgence and selection of different cell subpopulations derived from a common
progenitor cell. However, in one patient different alleles in two markers
at chromosome 9 were deleted, favoring an independent evolution of two recu
rring tumor cell clones. In summary, we could show that there is considerab
le genetic heterogeneity in early multifocal and recurring urothelial carci
noma and demonstrated the occurrence of two independent clones in at least
one patient as an indicator of possible initial oligoclonality of bladder c
ancer.