title: p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.
abstract: Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.
authors.affiliation: Department of Radiobiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima 732-0815, Japan. iwamoto@ref.or.j
authors.forename: K S
authors.initials: KS
authors.lastname: Iwamoto
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.forename: A
authors.initials: A
authors.lastname: Kurata
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtsuki
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Hosobe
authors.forename: K
authors.initials: K
authors.lastname: Doishita
authors.forename: T
authors.initials: T
authors.lastname: Manabe
authors.forename: S
authors.initials: S
authors.lastname: Hata
authors.forename: I
authors.initials: I
authors.lastname: Murakami
authors.forename: S
authors.initials: S
authors.lastname: Hata
authors.forename: S
authors.initials: S
authors.lastname: Itoyama
authors.forename: S
authors.initials: S
authors.lastname: Akatsuka
authors.forename: N
authors.initials: N
authors.lastname: Ohara
authors.forename: K
authors.initials: K
authors.lastname: Iwasaki
authors.forename: H
authors.initials: H
authors.lastname: Akabane
authors.forename: M
authors.initials: M
authors.lastname: Fujihara
authors.forename: T
authors.initials: T
authors.lastname: Seyama
authors.forename: T
authors.initials: T
authors.lastname: Mori
mesh_terms: D000368:Aged; D002470:Cell Survival / Q000528:radiation effects; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D009385:Neoplastic Processes; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013911:Thorium Dioxide / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D013911:Thorium Dioxide