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[Cancer Research 54, 784-788, February 1, 1994]
© 1994 American Association for Cancer Research
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Two Molecular Pathways to Transitional Cell Carcinoma of the Bladder1

Charles H. Spruck, III, Petra F. Ohneseit, Mirella Gonzalez-Zulueta, David Esrig, Noriomi Miyao, Yvonne C. Tsai, Seth P. Lerner, Christoph Schmütte, Allen S. Yang, Richard Cote, Louis Dubeau, Peter W. Nichols, Gregers G. Hermann, Kenneth Steven, Thomas Horn, Donald G. Skinner and Peter A. Jones2

Kenneth Norris Jr. Comprehensive Cancer Center, Departments of Biochemistry and Molecular Biology [C. H. S., P. F. O., M. G-Z., Y. C. T., S. P. L., C. S., A. S. Y., P. A. J.], Urology [D. E., N. M., D. G. S.], and Pathology [R. C., L. D., P. W. N.], University of Southern California, School of Medicine, Los Angeles, CA 90033, and Departments of Urology [G. G. H., K. S.] and Pathology [T. H.], Herlev Hospital, University of Copenhagen, DK-2730 Herlev Denmark

Noninvasive transitional cell carcinomas of the bladder can have two distinct morphologies suggesting they contain different genetic alterations. Papillary transitional cell carcinomas (Ta tumors) are often multifocal and only occasionally progress, whereas flat tumors (carcinomas in situ, CIS), frequently progress to invasive disease. We examined 216 bladder tumors of various stages and histopathologies for two genetic alterations previously described to be of importance in bladder tumorigenesis. Loss of heterozygosity of chromosome 9 was observed in 24 of 70 (34%) Ta tumors but was present in only 3 of 24 (12%) CIS and dysplasia lesions (P = 0.04). In contrast, only 1 of 36 (3%) Ta tumors contained a p53 gene mutation compared to 15 of 23 (65%) CIS and dysplasias (P < 0.001), a frequency comparable to that observed in muscle invasive tumors (25 of 49; 51%). The presence of p53 mutations in CIS and dysplasia could explain their propensities to progress since these mutations are known to destabilize the genome. Analysis of several tumor pairs involving a CIS and an invasive cancer provided evidence that the chromosome 9 alteration may in some cases be involved in the progression of CIS to more invasive tumors, in addition to its role in the initiation of Ta tumors. However, the CIS and secondary tumor were found to contain different genetic alterations in some patients suggesting divergent progression pathways. Bladder carcinogenesis may therefore proceed through two distinct genetic alteration pathways responsible for generating superficial tumors with differing morphologies and pathologies.

1 Supported by USPHS Grant R35 CA49758 from the National Cancer Institute.

2 To whom requests for reprints should be addressed, at the Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033-0800.

Received 9/20/93. Accepted 12/17/93.




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Am. J. Pathol., November 1, 1998; 153(5): 1615 - 1621.
[Abstract] [Full Text] [PDF]

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T. R. Yeager, S. DeVries, D. F. Jarrard, C. Kao, S. Y. Nakada, T. D. Moon, R. Bruskewitz, W. M. Stadler, L. F. Meisner, K. W. Gilchrist, et al.
Overcoming cellular senescence in human cancer pathogenesis
Genes & Dev., January 15, 1998; 12(2): 163 - 174.
[Abstract] [Full Text]

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S. M. Cohen
Urinary Bladder Carcinogenesis
Toxicol Pathol, January 1, 1998; 26(1): 121 - 127.
[Abstract] [PDF]

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D. Esrig, D. Elmajian, S. Groshen, J. A. Freeman, J. P. Stein, S.-C. Chen, P. W. Nichols, D. G. Skinner, P. A. Jones, and R. J. Cote
Accumulation of Nuclear p53 and Tumor Progression in Bladder Cancer
N. Engl. J. Med., November 10, 1994; 331(19): 1259 - 1264.
[Abstract] [Full Text]

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R. J. Homer, W.J. Braund, R. H. Hruban, P. van der Riet, and D. Sidransky
Hubert Humphrey's Bladder Cancer
N. Engl. J. Med., September 29, 1994; 331(13): 880 - 881.
[Full Text]

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C A Reznikoff, C Belair, E Savelieva, Y Zhai, K Pfeifer, T Yeager, K J Thompson, S DeVries, C Bindley, and M A Newton
Long-term genome stability and minimal genotypic and phenotypic alterations in HPV16 E7-, but not E6-, immortalized human uroepithelial cells.
Genes & Dev., September 15, 1994; 8(18): 2227 - 2240.
[Abstract] [PDF]

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 NEJMHome page
R. H. Hruban, P. van der Riet, Y. S. Erozan, and D. Sidransky
Molecular Biology and the Early Detection of Carcinoma of the Bladder -- The Case of Hubert H. Humphrey
N. Engl. J. Med., May 5, 1994; 330(18): 1276 - 1278.
[Full Text]


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