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

Ikuo Wada, Hajime Horiuchi, Masaya Mori, Yuichi Ishikawa, Manabu Fukumoto, Takesaburo Mori, Yo Kato, Tomoyuki Kitagawa, Rikuo Machinami

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15 Citations (Scopus)

Abstract

Epidemiological studies have revealed that malignant tumors occur in the liver approximately 20 years after injection of Thorotrast. We investigated genetic changes in the TP53 gene (formerly known as p53) in malignant liver tumors related to Thorotrast to cast light on the mechanisms of α-particle carcinogenesis. A total of 19 autopsy cases of liver malignancies [11 hepatocellular carcinomas (HCC), 5 cholangiocellular carcinomas (CCC) and 3 angiosarcomas (AS)] were analyzed. Using archival tissues, loss of heterozygosity (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 terms of polymorphism, and 4 cases showed LOH (3 HCC and 1 AS). Eight cases showed 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 action of α 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 α particles but rather by indirect effects that may have been due to cycles of necrosis and regeneration.

Original languageEnglish
Pages (from-to)S125-S127
JournalRadiation Research
Volume152
Issue number6 SUPPL.
DOIs
Publication statusPublished - 1999 Dec

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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