P53 MUTATIONS IN PRIMARY HEPATIC ANGIOSARCOMAS NOT ASSOCIATED WITH VINYL-CHLORIDE EXPOSURE

Angiosarcomas of the liver are rare, malignant cancers composed of neo plastic blood vessels, Human hepatic angiosarcomas have been associate d with liver cirrhosis or exposure to vinyl chloride, Thorotrast or ar senic, A recent analysis of six hepatic angiosarcomas associated with vinyl chloride exposure found three mutations and all were A:T --> T:A transversions, which are otherwise uncommon in human cancers, To test the specificity of this mutation spectrum, we analyzed 21 hepatic ang iosarcomas not associated with vinyl chloride exposure, Four cases wer e exposed to Thorotrast, none had a history of arsenic exposure and th e rest were sporadic, Exons 5-8 of the p53 gene were amplified by poly merase chain reaction, and the products were sequenced directly, Two G :C --> A:T transitions were found in two tumors: TGC(cys) --> TAC(tyr) in codon 141 and CAA(gln) --> TAA(stop) in codon 136. Neither mutatio n was associated with Thorotrast exposure, These data indicate that p5 3 mutations are uncommon in sporadic hepatic angiosarcomas (2/21, 9%), and the mutational profile is consistent with endogenous mechanisms, Both features support the evidence linking vinyl chloride exposure to hepatic angiosarcomas containing an increased frequency of p53 mutatio ns with a mutational spectrum (i.e. A:T --> T:A transversions) charact eristic of chloroethylene oxide, a carcinogenic metabolite of vinyl ch loride.