Journal Article

p53 mutations in tumor and non-tumor tissues of Thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver

Keisuke S. Iwamoto, Shiho Fujii, Akihiko Kurata, Makoto Suzuki, Tohru Hayashi, Yuji Ohtsuki, Yuhei Okada, Michihiko Narita, Masanori Takahashi, Sadahiro Hosobe, Kenji Doishita, Toshiaki Manabe, Sakae Hata, Ichiro Murakami, Satoru Hata, Shinji Itoyama, Seiya Akatsuka, Nobuya Ohara, Keisuke Iwasaki, Hisamasa Akabane, Megumu Fujihara, Toshio Seyama and Takesaburo Mori

in Carcinogenesis

Volume 20, issue 7, pages 1283-1291
Published in print July 1999 | ISSN: 0143-3334
Published online July 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.7.1283
p53 mutations in tumor and non-tumor tissues of Thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver

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Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as α-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 α-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 α-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 α-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.

Keywords: LET, linear energy transfer; SSCP, single strand conformation polymorphism.

Journal Article.  6515 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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