HIGH-FREQUENCY OF CHROMOSOME 9P ALLELIC LOSS AND CDKN2 TUMOR-SUPPRESSOR GENE ALTERATIONS IN SQUAMOUS-CELL CARCINOMA OF THE BLADDER

Background: In the Western Hemisphere, 90% of bladder cancers are tran sitional cell carcinomas, while only 7% are classified as squamous cel l carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is e ndemic, squamous cell carcinoma is the most common bladder cancer as w ell as the most common cancer in men. Purpose: We planned experiments to understand the genetic defects underlying the development of squamo us cell carcinoma and to determine if the morphologically and clinical ly distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations. Methods: Squamous cell carcinoma specimens from highrisk (Egypt, n = 19) and lo w-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Hom ozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN 2 and p53 (also known as TP53) genes were analyzed by single-strand co nformation polymorphism and DNA sequencing. Immunohistochemical staini ng of p53 protein was also performed. Allelic losses in chromosome arm s 9p, 9q, and 17p were determined by microsatellite analysis. Results: Homozygous deletions and sequence mutations in the CDKN2 gene were fo und in 67% (eight of 12) of squamous cell carcinoma specimens, a frequ ency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p , where CDKN2 resides, were found in 92% (11 of 12) of uncultured squa mous cell carcinomas, while only about 39% (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with n o change in 9q were found in 92% (10 of 11) of squamous cell carcinoma s compared with only 10% (11 of 110) of transitional cell carcinomas ( P<.001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive tra nsitional cell carcinomas (60%), but the type and position of mutation s differed between the two tumor types. Allelic losses in chromosome a rm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38%) than in invasive transitional cell carc inomas (60%). Conclusions: Our results suggest that a putative tumor s uppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previ ously reported data on transitional tell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggestin g that distinct underlying genetic defects may explain, at least in pa rt, the pathological differences between the two tumors of the bladder epithelium. Implications: Development of diagnostic and therapeutic s trategies for squamous cell carcinoma of the bladder based on its dist inct genetic alterations is warranted.