TY - JOUR
T1 - Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer
AU - Stoehr, Robert
AU - Wissmann, Christoph
AU - Suzuki, Hiromu
AU - Knuechel, Ruth
AU - Krieg, Rene C.
AU - Klopocki, Eva
AU - Dahl, Edgar
AU - Wild, Peter
AU - Blaszyk, Hagen
AU - Sauter, Guido
AU - Simon, Ronald
AU - Schmitt, Ruediger
AU - Zaak, Dirk
AU - Hofstaedter, Ferdinand
AU - Rosenthal, Andre
AU - Baylin, Stephen B.
AU - Pilarsky, Christian
AU - Hartmann, Arndt
N1 - Funding Information:
We thank Ms Andrea Schneider, Ms Monika Kerscher, Ms Martina Mirlader and Mr Rudolf Jung for excellent technical assistance in tissue preparation, sequence analysis and immunohistochemistry. This work was supported by the following grants: 10-1598/HA2 (Dr Mildred Scheel-Stiftung for Cancer Research); Kn 263/7-2 (German Research Foundation DFG); 01KW9940 (BMBF).
PY - 2004
Y1 - 2004
N2 - Many molecular alterations are known to occur in urothelial carcinoma of the bladder, but their significance for tumor progression is poorly understood. Deletions of chromosome 8p are frequently found in several tumor types and are often associated with progressive disease. In all, 99 bladder tumors were screened for deletions at 8p using loss of heterozygosity (LOH) and multicolor fluorescence in situ hybridization FISH analyses. Allelic loss on chromosome 8p in at least one marker was found in 25/99 (25%) tumors. There was a significant correlation of 8p deletions with invasive tumor growth and a highly significant association with papillary growth pattern in patients with invasive disease. cDNA array analyses revealed that secreted Frizzled-related protein 1 (sFRP1), an antagonist of Frizzled receptors and Wnt pathway activation on chromosome 8p12-11.1, is frequently downregulated in bladder cancer. To investigate sFRP1 as a candidate for a putative progression-related gene on 8p, urothelial cell lines and primary urothelial carcinomas were screened for sFRP1 expression using quantitative real-time PCR, Northern blot, immunofluorescence and immunohistochemistry (IHC). Of the investigated bladder cancers, 38% showed loss of sFRP1 expression by quantitative RT-PCR. Evaluation of the protein expression by IHC using tissue microarrays containing 776 bladder cancers revealed loss or strong reduction of sFRP1 expression in 66% of cases. SFRP1 loss was associated with higher tumor stage and grade and shorter overall survival. In addition, loss of sFRP1 was an independent indicator of poor survival in patients with papillary but not with muscle invasive bladder cancer. There were neither mutations in the coding region of sFRP1 nor homozygous deletions at 8p12-11.21. However, promoter methylation was detected using methylation-specific PCR in 29% of cases. In conclusion, we could show a close correlation of chromosome 8p deletions and progression of papillary bladder tumors. The sFRP1 gene on chromosome 8p12-11.1 could be a candidate gene for the predicted, progression-related tumor suppressor gene in bladder cancer and could contribute to urothelial carcinogenesis.
AB - Many molecular alterations are known to occur in urothelial carcinoma of the bladder, but their significance for tumor progression is poorly understood. Deletions of chromosome 8p are frequently found in several tumor types and are often associated with progressive disease. In all, 99 bladder tumors were screened for deletions at 8p using loss of heterozygosity (LOH) and multicolor fluorescence in situ hybridization FISH analyses. Allelic loss on chromosome 8p in at least one marker was found in 25/99 (25%) tumors. There was a significant correlation of 8p deletions with invasive tumor growth and a highly significant association with papillary growth pattern in patients with invasive disease. cDNA array analyses revealed that secreted Frizzled-related protein 1 (sFRP1), an antagonist of Frizzled receptors and Wnt pathway activation on chromosome 8p12-11.1, is frequently downregulated in bladder cancer. To investigate sFRP1 as a candidate for a putative progression-related gene on 8p, urothelial cell lines and primary urothelial carcinomas were screened for sFRP1 expression using quantitative real-time PCR, Northern blot, immunofluorescence and immunohistochemistry (IHC). Of the investigated bladder cancers, 38% showed loss of sFRP1 expression by quantitative RT-PCR. Evaluation of the protein expression by IHC using tissue microarrays containing 776 bladder cancers revealed loss or strong reduction of sFRP1 expression in 66% of cases. SFRP1 loss was associated with higher tumor stage and grade and shorter overall survival. In addition, loss of sFRP1 was an independent indicator of poor survival in patients with papillary but not with muscle invasive bladder cancer. There were neither mutations in the coding region of sFRP1 nor homozygous deletions at 8p12-11.21. However, promoter methylation was detected using methylation-specific PCR in 29% of cases. In conclusion, we could show a close correlation of chromosome 8p deletions and progression of papillary bladder tumors. The sFRP1 gene on chromosome 8p12-11.1 could be a candidate gene for the predicted, progression-related tumor suppressor gene in bladder cancer and could contribute to urothelial carcinogenesis.
KW - Bladder cancer
KW - Chromosome 8
KW - LOH
KW - Promoter methylation
KW - TMA
KW - sFRP1
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U2 - 10.1038/labinvest.3700068
DO - 10.1038/labinvest.3700068
M3 - Article
C2 - 14968126
AN - SCOPUS:2342574321
SN - 0023-6837
VL - 84
SP - 465
EP - 478
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 4
ER -