MUTATIONAL SPECTRUM IN THE P53 GENE IN BLADDER-TUMORS FROM THE ENDEMIC AREA OF BLACK FOOT DISEASE IN TAIWAN

An elevated risk of bladder cancer has been reported in the endemic re gion of 'black foot disease' on the southwest coast of Taiwan and may be related to high arsenic levels in artesian well water. Thirteen uro thelial tumors from this endemic region were examined for mutations in exons 5 - 8 of the p53 gene to identify the effects of possible exoge nous factors at the DNA level. DNA was extracted from archival tissue after microdissection of tumors and analyzed by PCR-SSCP (polymerase c hain reaction-based single strand conformation polymorphism), followed by direct sequencing. Eight cases (62%) showed mutations and 9 of the 10 point mutations observed were transitions. The type and position o f the mutations were not significantly different when compared with th e spectra of p53 mutations previously reported for transitional cell c arcinomas (TCCs). However, two of the mutations were CGC --> CAC base changes at codon 175, a mutational hotspot for many tumor types but pr eviously unreported in TCCs except in cases associated with inflammato ry agents. Three of the tumors examined were found to contain double m utations, a relatively rare mutagenic event in human cancers. Our resu lts suggest that the agents responsible for the high risk of bladder c ancer in the black foot disease region may operate through an inflamma tion-based mechanism which increases the amount of DNA damage per muta genic event.