High rate of small TP53 mutations and infrequent loss of heterozygosity inmalignant liver tumors associated with thorotrast: Implications for alpha-particle carcinogenesis

Epidemiological studies have revealed that malignant tumors occur in the li ver approximately 20 years after injection of Thorotrast. We investigated g enetic changes in the TP53 gene (formerly known as p53) in malignant liver tumors related to Thorotrast to cast light on the mechanisms of cu-particle carcinogenesis, A total of 19 autopsy cases of liver malignancies [11 hepa tocellular carcinomas (HCC), 5 cholangiocellular carcinomas (CCC) and 3 ang iosarcomas (AS)] were analyzed. Using archival tissues, loss of heterozygos ity (LOH) at the 17p13 locus was analyzed. Then single-strand conformation polymorphism analysis and sequencing were performed to detect mutations in exons 5 to 8 of the TP53 gene. As a result, 15 cases were informative in te rms of polymorphism, and 4 cases showed LOH (3 HCC and 1 AS), Eight cases s howed 9 mutations in exons and 2 in introns: 7 transitions (6 HCC and 1 CCC ), 2 transversions (1 HCC and 1 AS), and 2 deletions (2 HCC). The direct ac tion of alpha particles is thought to result in relatively large deletions such as those detected by LOH, Therefore, the low frequency of such changes (27%) compared to point mutations (47%) suggests that the genetic changes in the TP53 gene in the liver tumors related to Thorotrast were not caused mainly by direct actions of alpha particles but rather by indirect effects that may have been due to cycles of necrosis and regeneration. (C) 1999 by Radiation Research Society.