MUTATIONS IN THE P53 GENE IN SCHISTOSOMAL BLADDER-CANCER - A STUDY OF92 TUMORS FROM EGYPTIAN PATIENTS AND A COMPARISON BETWEEN MUTATIONAL SPECTRA FROM SCHISTOSOMAL AND NONSCHISTOSOMAL UROTHELIAL TUMORS

Much of bladder cancer in East Africa and the Middle East is attribute d to chronic urinary infection with Schistosoma haematobium ('schistos omiasis'). Most schistosomal bladder cancer (SEC) is squamous cell car cinoma (SCC) and occurs in the fifth decade of life. In contrast, nons chistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcino ma (TCC). To shed light on the mechanisms underlying these different p atterns of bladder cancer we looked for mutations in the p53 gene in S BC from 92 patients in Egypt, where schistosomiasis is hyperendemic. P atients' mean age at presentation of bladder cancer was 49.4 +/- 9.9 y ears and 90% had a clinical history of schistosomiasis and/or histolog ical evidence of schistosomal eggs adjacent to the carcinoma. There we re 53 SCC, 23 TCC, 13 adenocarcinomas and three other carcinomas. Thir ty patients had tumours with mutations in exons 5-8 of the p53 gene: 1 7/53 SCC, 8/23 TCC, 4/13 adenocarcinomas and 1/3 other tumours. Of 19 mutations in SCC, 16 were base pair substitutions (BPS), two were dele tions and one an insertion. Two tumours each contained two mutations. Of the BPS, nine were transitions at CpG dinucleotides and two were G- ->T transversions. All the mutations in TCC were BPS: four were transi tions at CpG dinucleotides and three were G-->C transversions. One TCC had two mutations. Of four adenocarcinomas with mutations, two had tr ansitions at CpG dinucleotides. Of the 30 BPS mutations, 16 were trans itions at CpG dinucleotides, of which 12 were C-->T. We combined these 33 mutations with six obtained from Egyptian SCC reported by Habuchi et al. (Cancer Res., 53, 3795-3799, 1993) to compile a mutational spec trum. This was compared with a NSBC spectrum assembled from 118 mutati ons reported in the literature. The proportion of BPS at CpG dinucleot ides was significantly higher in SEC than in NSBC (18/34 versus 25/103 , P = 0.003). There was also a bias away from mutations in exons 7 and 8 towards mutations in exons 5 and 6. We suggest that the excess of t ransitions at CPG dinucleotides in SEC results from nitric oxide (NO) produced by the inflammatory response provoked by schistosomal eggs. N O could produce such mutations directly, by deamination of 5-methylcyt osine, and indirectly, following conversion to nitrate, bacterial redu ction to nitrite and endogenous formation of urinary N-nitroso compoun ds. These produce O-6-alkylguanines in DNA, leading to very high rates of G:C-->A:T transitions, a process possibly augmented by inefficient repair of alkylated bases at CpG dinucleotides.