MUTATIONS IN THE TUMOR-SUPPRESSOR GENE P53 IN HUMAN LIVER-CANCER INDUCED BY ALPHA-PARTICLES

The p53 tumor suppressor gene is mutated in varying fractions of almos t all tumor types studied, The rate of mutations and the mutational sp ectrum in some tumors are specific for environmental mutagens assumed to be involved in the carcinogenic process, Thus, hepatocellular carci nomas supposedly induced by aflatoxin exposure often contain a specifi c point mutation in codon 249, and in lung cancers of miners with heav y radon exposure, another specific point mutation in codon 249 suggest ive of an alpha-particle-specific mutation has been shown, The interpr etation of studies linking the mutational spectrum with specific envir onmental exposures is complicated by the multifactorial or unknown gen esis of most tumors, However, people given injections of the X-ray con trast medium Thorotrast (Th) in the past have experienced an enormous risk of liver tumors, and virtually all of these are supposedly induce d by alpha-particles from the decay of Th-232. The examination of thes e tumors may provide evidence as to whether specific p53 point mutatio ns are relevant in alpha-particle carcinogenesis, Therefore, we collec ted paraffin-embedded, formalin-fixed archival tissues from 18 hepatoc ellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients, The tissues were analyzed for p53 p rotein expression by immunohistochemical staining by using the mAb DO- 7 and for mutations of exons 5-8 by PCR and constant denaturant gel el ectrophoresis, G-->T transversions of the third base of codon 249 of t he p53 gene were specifically screened for by restriction enzymes, No high score for p53 protein expression (i,e,, positive staining of >20% of examined cells) was observed; lower scores were seen in 5 of 18 (2 8%) hepatocellular carcinomas, 1 of 9 (11%) cholangiocarcinomas, and 0 of 8 (0%) hepatic angiosarcomas. Only one p53 mutation, a heterozygou s T-->G transversion of the first base of codon 176, occurred in a hep atocellular carcinoma, The rate of p53 paint mutations in alpha-partic le-induced liver tumors seems to be lower than in European hepatocellu lar carcinomas in general, The study does not exclude the possibility that alpha-particle carcinogenesis may involve inactivation of p53 by gross deletions of the gene, but it speaks against the proposed specif icity of point mutations of codon 249 in cancer supposedly induced by alpha-particles from radon progeny.