Comparison of genetic changes in schistosome-related transitional and squamous bladder cancers using comparative genomic hybridization
M. Muscheck,
H. Abol-Enein1,
K. Chew,
D. Moore, II,
V. Bhargava2,
M.A. Ghoneim1,
P.R. Carroll3 and
F.M. Waldman4
UCSF Cancer Center, Box 0808, University of California San Francisco, San Francisco, CA 94143-0808, USA,
1 Urology and Nephrology Center, University of Mansoura, Mansoura, Egypt,
2 Department of Pathology , VA Medical Center, San Francisco, CA and
3 Department of Urology, University of California San Francisco, San Francisco, CA 94143-0738, USA
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Abstract
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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.
Abbreviations: CGH, comparative genomic hybridization; DOP-PCR, degenerate oligonucleotide primed polymerase chain reaction; SCC, squamous cell carcinomas; TCC, transitional cell carcinomas.
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Introduction
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Schistosome-related bladder carcinoma is a major oncologic problem in Egypt, many parts of the Middle East and Africa. Egypt represents a hyperendemic area of schistosome infection, having an overall prevalence of ~50%. In Egypt, the frequency of schistosome-related bladder carcinoma accounts for 31% of all cancers (39 and 11% of cancers in males and females, respectively) (1,2).
Compared with non-schistosome-related bladder cancer, schistosome-related bladder cancer has different clinical and pathological features. Its incidence reaches a peak between the third and fifth decades of life, whereas non-schistosome-related bladder cancer is a disease of the elderly and is seldom seen in the young or middle-aged. Over 90% of schistosome-related bladder cancers present with invasive disease (pT2-4), forming relatively highly differentiated bulky solid tumors. In non-schistosome-related bladder cancer, ~70% present as superficial tumors (pTa, pTis, pT1) (35).
Schistosome-related bladder cancer differs from non- schistosome-related bladder cancer most strikingly in its squamous cell differentiation. Schistosome-related tumors are largely squamous cell carcinomas (SCC, 5070%), followed by transitional cell carcinoma (TCC, 3050%) and adenocarcinoma (2%) (4,5). In non-schistosome-related bladder cancer, TCC greatly outnumber SCC and adenocarcinoma (90, 7 and 3%, respectively) (6,7).
Several studies comparing schistosome-related bladder cancer and non-schistosome-related bladder cancer have been reported, mostly focusing on differences between the squamous subgroup of schistosome-related bladder cancer and TCCs of non-schistosome-related origin (811). Few studies have compared schistosome-related bladder tumors of TCC and squamous subgroups (1216).
We have previously reported chromosomal copy number alterations in TCC of US origin detected by comparative genomic hybridization (CGH) (1719). In the current study, CGH was used to identify genomic alterations in both transitional and squamous subgroups of schistosome-related bladder cancers.
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Materials and methods
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Tumor samples
Tumor specimens were obtained from the Urology and Nephrology Center, University of Mansoura, Egypt. A cohort of 54 patients with schistosome-related bladder carcinomas were evaluated. All samples were from primary tumors following radical cystectomy. Twenty-six SCC tumors and 28 TCC tumors were studied. All tumors were stage pT2-4, N0, M0. No preoperative radiation therapy or chemotherapy was administered to any of the patients. Tumor stage and grade were defined according to UICC (20) and World Health Organization classifications (21). All samples were from formalin-fixed, paraffin-embedded archival specimens. Representative 5 µm H&E-stained sections from each tumor were reviewed by a pathologist (V.B.) to identify the histological type of tumor, either transitional or squamous. Mixed tumors were excluded from the study. Schistosomiasis infection was confirmed by the presence of ova in every case.
Tissue dissection and DNA extraction
Areas for microdissection were identified within each tumor as described previously (22,23). Regions with homogeneous tumor and minimal contaminating normal cells were used. Areas of necrosis, common in schistosome-related cancers (24), were excluded. Tumor was dissected from a single 5 µm section, and DNA was extracted by 3 day proteinase K treatment. Reference DNA for CGH was isolated from blood leukocytes of healthy male and female donors as described previously (22,25).
Polymerase chain reaction amplification
Amplification of the microdissected DNA was based on the degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) protocol as described previously (23,26). A 1 µl aliquot of microdissected and extracted DNA was subjected to five cycles of sequenase extension, followed by 35 cycles of TAQ polymerase (Boehringer Mannheim) amplification. DNA sizes ranged from 200 to 2000 bp.
Comparative genomic hybridization
CGH was done as described previously (17,22). Briefly, DOP-PCR-amplified tumor and normal reference DNA were labeled by nick translation with digoxigenin-11-dUTP (Boehringer Mannheim) and fluorescein 12-dUTP (DuPont). Each CGH experiment included normal DNA as a negative control and a tumor cell line DNA (MPE600) as a positive control. All of the tumor samples were hybridized a second time with biotin-16-dUTP-labeled normal reference DNA as a control for hybridization artifacts (`inverse' labeling CGH). Comparison of the results of these two hybridizations was required to confirm the presence of copy number aberrations.
The digoxigenin-labeled tumor DNA was visualized with anti-digoxigenen Fab fragments conjugated to rhodamine (Boehringer Mannheim) in the first hybridization, and for the `inverse' labeling the biotinylated normal DNA was detected with FITCavidin (Vector Laboratories). Chromosomes were counterstained with 4,6-diamidino-2-phenylindole dihydrochloride in an antifade solution.
Image acquisition and analysis
CGH hybridization results were analyzed with our previously described image analysis system (27). Successful hybridizations were judged by the intensity, smoothness and homogeneity of signals. At least five metaphase spreads were chosen for image acquisition.
Low level gains of DNA-sequences were defined as chromosomal regions where both the mean test to reference fluorescence ratio and its SD were above 1.25, whereas losses were defined as regions where both the mean and its SD were below 0.80. Subchromosomal regions where the ratio exceeded 1.5 were considered to represent high-level amplification. The use of `inverse' CGH allowed greater confidence in making these interpretations. All changes must have been seen in both hybridizations. Interpretations at 1pter, 19 and 22 required careful examination of all chromosome profiles, because these loci were likely to show a higher variability in their ratios.
Statistics
Differences in DNA copy number aberrations between SCC and TCC were compared using the
2 test applied to 2x2 contingency tables. We also used a
2 test to determine whether the observed ratios of copy number aberrations in TCC to SCC tumors differed significantly from the overall ratio of 14.4:8.2 (i.e. ratio = 1.76). For each chromosome arm and type of aberration (gain or loss), maximum likelihood was used to find a proportion P which best fit the observed data under the constraint that when there are NP aberrations in SCC tumors, then there must be 1.76 NP aberrations in TCC tumors. For example, we observed 10 of 28 TCC tumors (36%) with loss of 17p compared with 14 of 26 SCC tumors (54%). These two frequencies do not differ when compared directly. However, when they are compared under the restriction that there should be 1.76 TCC aberrations for every SCC aberration, the probability of observing such a disparity in aberration frequencies is 0.001.
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Results
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The pathologic stage and grade of the tumors are shown in Table I
. Consistent with our selection criteria, the stage distribution was similar in the two histologic types. However, the proportion of grade I tumors was higher in SCC (62%) than in the TCC subgroup (4%). This may have been due to the requirement for sufficient differentiation in the squamous group to allow discrimination from transitional histology.
DNA sequence copy number aberrations detected by CGH in these schistosome-related SCC and TCC are shown in Figure 1
. Only one of the 54 tumors studied (an SCC) showed an absence of CGH abnormalities.


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Fig. 1. CGH alterations in schistosome-related bladder cancer; SCC (a) and TCC (b). Lines to the left of each chromosome ideogram represent losses and lines to the right represent gains. High level gains are represented by thick bars.
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On average, there were 8.2 aberrations per tumor for squamous tumors (range 017), and 14.4 aberrations per tumor for transitional cell tumors (range 229). This represents a highly significant difference (P < 0.001) between the tumor types. The SCC had 2.9 gains (range 08) and 4.5 deletions (range 011) per tumor, whereas the TCC had 5.8 gains (range 113) and 8.0 deletions (range 116) per tumor. A summary of the prevalence of specific chromosomal gains and losses is shown in Table II
. For all tumors combined, 8p, 8q+ and 18q were the most common aberrations. In addition, 5q, 9p, 10q, 11p, 11q and 17q+ were frequent in TCC tumors, whereas 17p and 18p were especially frequent in SCC tumors.
Table III
shows a comparison of alterations in TCC versus SCC. Without correction for the total number of aberrations in each group, there were significantly more losses at chromosome arms 5q, 6q, 10q, 11p and 11q, and significantly more gains at 1q and 17q. However, after correction for the differences in the total number of changes in each group, there were significantly more losses involving chromosome arms 17p (P = 0.001), 18p (P = 0.03) and 21q (P = 0.03) in the SCC group. 11p loss was so much more frequent in TCC than SCC that the difference remained significant even after correction.
High level amplifications (green to red ratio >1.5) of small chromosome regions were found in eight SCC tumors, and 15 TCC tumors. Most frequently found amplifications included 1q21q23 (n = 2), 6p22 (n = 2), 8q22q23 (n = 4), 11q13 (n = 3) and 12q14q21 (n = 3) for TCC tumors, and 8q22q23 (n = 2) for SCC tumors.
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Discussion
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Carcinoma of the bladder in Western countries is thought to be caused by chronic exposure of the urothelium to exogenous carcinogens which are concentrated in the urine, leading to genetic damage. In contrast, schistosome-related bladder cancer is thought to be related to the chronic inflammatory response which occurs following schistosomal infection. Western bladder cancer predominantly shows transitional cell histology, while schistosome-related cancer is largely of squamous type. Little is known of the genetic distinction between these two tumor types. In this study, we show that squamous and transitional cancer histologies in schistosome-infected patients show distinct patterns of chromosomal alterations.
CGH has been used to characterize carcinomas of the urinary bladder unassociated with schistosome infection in several previous studies (18,19,2831), but has not yet been performed in schistosome-related tumors. Kallioniemi et al. (18) and Hovey et al. (19) reported CGH alterations in two small sets of transitional cell muscle invasive cancers (n = 20 and n = 22, respectively), whereas Richter et al. (30) reported results from a larger group of such tumors. The mean number of alterations detected in these studies (811 alterations per tumor) was less than were present in our schistosome-related transitional cell tumors (14 per tumor). However, the specific CGH alterations in the current study which were common to both the TCC and SCC groups, 5p+, 5q, 7+, 8p, 8q+, 9p and 18q, were also among the most common group in Western transitional cell tumors.
Deletion of 17p was significantly increased in SCC (54%) compared with TCC (36%) (P = 0.001). Considering the reduced mean number of CGH alterations in SCC (8.2) compared with TCC (14.6), the greater frequency of 17p deletions in SCC suggests that this alteration may play a specific role in SCC tumorigenesis. p53 is the most likely candidate gene target associated with loss of 17p, reflected in the high frequency of p53 abnormalities detected by immunohistochemistry in invasive tumors (3855%) (3234). Our data are consistent with results reported by Habuchi et al. (9), who found p53 mutations in 86% of schistosome-related SCC, compared with 33% in non-schistosome-related TCC. Gonzalez-Zulueta et al. (11) found p53 mutations in 60% of their SCC tumors (not all of which were schistosome related), although they found 17p LOH in only 38%. Unlike our observation of increased 17p loss in SCC compared with TCC using CGH, Shaw et al. (35) detected a greater frequency of 17p LOH in schistosome-related TCC than in schistosome-related SCC (90 versus 43%), using microsatellite analysis. This may have been due to a group of low stage SCC tumors in their patient cohort. In contrast to these findings, a recent study by El-Rifai et al. (36) found no deletions involving 17p in their schistosome-related SCC or TCC. The absence of 17p losses in their tumors may have been due to reduced sensitivity resulting from normal cell contamination in their non-microdissected specimens. Our finding of 36% 17p deletions in schistosome-related TCC is similar to findings of Kallioniemi et al. (18), showing 17p loss in 27% of Western T2T4 TCC tumors by CGH, and to Richter et al. (30) reporting 25%.
Immunohistochemical studies have shown inconsistent results for p53 overexpression in schistosome-related bladder cancers. Chaudhary et al. (15) describe p53 overexpression in 82% of schistosome-related TCC tumors and in 70% of schistosome-related SCC cases, and Pycha et al. (37) report p53 overexpression in a high proportion of schistosome-related tumors (82% of SCC and 74% of TCC), as well as in non-schistosome-related TCC (81%). However, Osman et al. (24) detected overexpression of p53 in only 20% of both schistosome-related histologic groups. These discrepancies might be explained by the use of different antibodies, staining methodologies, and scoring cut-points, although differences in the patient populations are also possible.
Although deletions involving chromosome 9 are frequently reported in TCC of the bladder (29,31,38,39), it is unclear whether genes on the short or long arm are being selected for during tumor development and progression. It is clear that p16 (CDKN2), on 9p21, is specifically altered in bladder cancers, although the target on the long arm is still uncertain. The current study of schistosome-related tumors showed a higher frequency of 9p loss than 9q loss in both tumor types (54% 9p versus 32% 9q in TCC, and 27% 9p versus 12% 9q in SCC). The lower rates of chromosome 9 deletions in SCC are consistent with the reduced mean number of alterations in SCC compared with TCC in our study. Microsatellite analysis in schistosome-related tumors reported by Shaw et al. (35) showed a similar predominance of 9p versus 9q losses (73% 9p versus 45% 9q in TCC, and 67% 9p versus 44% 9q in SCC). Gonzalez-Zulueta et al. (11) reported a homozygous deletion of p16 in six of nine schistosome-related SCC tumors, and found some alteration of 9p (homozygous or hemizygous loss) in 92% of SCC and in 39% of TCC tumors. Tamimi et al. (40) reported 53% of 46 schistosome-related bladder tumors showed a homozygous deletion of p16. Tsutsumi et al. (41) have reported p16 deletion in 52% of SCC of the bladder unrelated to schistosome infection.
Chromosome 11 was frequently deleted in schistosome-related TCC (50% 11p and 46% 11q), but not in schistosomal SCC (4% 11p and 15% 11q). Shaw et al. (35) reported similar LOH data for schistosome-related TCC (50% 11p versus 30% 11q), but detected higher rates of loss in schistosome-related SCC (24% on 11p versus 34% on 11q). Previous studies suggest that 11p is correlated with muscle invasion in Western tumors (38,42).
11q13 is the locus of cyclin D1 and EMS1 genes and has been reported as commonly amplified in bladder carcinomas (43,44). We found gains and amplifications in both tumor subgroups at that specific locus (29% in TCC and 12% in SCC). Osman et al. (24) reported similar findings using immunohistochemistry, with lower frequencies of cyclin D1 overexpression in schistosome-related SCC (22%) compared with schistosome-related TCC (38%). Their study reported a significant association between cyclin D1 overexpression and deep muscle invasion, Ki67 high proliferative index and high tumor grade. We report somewhat fewer alterations on 11q13 in SCC tumors than do Osman et al. (24), perhaps related to mechanisms other than DNA amplification leading to cyclin D1 overexpression.
Few studies have detected common deletions on chromosome arms 18p and 21q in bladder carcinomas. We found both alterations to be significantly higher in SCC than TCC tumors. Interpretation of differences in 21q deletions is difficult due to a low number of alterations (19% of SCC versus 7% of TCC tumors).
This study was designed to compare schistosome-related squamous and transitional cell tumors which were matched for stage. However, this selection resulted in a disparity in their pathologic grades, with the squamous tumors showing reduced grade compared with the transitional tumors (Table I
). This might account for some of the difference in the mean number of alterations found in the two tumor groups. Squamous cell tumors are defined by their specific histologic pattern. There must be sufficient differentiation to identify the typical combination of individual cell keratinization, keratin pearls and intercellular bridges. Non-keratinizing areas may not be distinguishable from high grade TCC (45). Many schistosome-related bladder cancer tissues show both squamous and transitional differentiation or even have an additional adenocarcinoma pattern. These questionable or mixed patterns were excluded from this study to assure more homogeneous groups. These requirements resulted in a low grade distribution for SCC (grade I and II in 96%, Table I
). In contrast, TCC have a distinct differentiation pattern that can be recognized in moderate to undifferentiated tumor cells, and low grade muscle invasive TCC are rarely seen. 96% of the TCC analyzed were thus grade II or III (Table I
).
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Notes
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4 To whom correspondence should be addressed Email: waldman{at}cc.ucsf.edu 
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Acknowledgments
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This work was supported by NCI grant CA 47537.
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Received March 6, 2000;
revised June 9, 2000;
accepted June 14, 2000.