Carcinogenesis, Vol. 20, No. 7, 1283-1291,
July 1999
© 1999 Oxford University Press
Carcinogenesis |
p53 mutations in tumor and non-tumor tissues of Thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver
Department of Radiobiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima 732-0815,
1 Department of Pathology, Osaka National Hospital, Osaka,
2 Department of Pathology, Shizuoka General Hospital, Shizuoka,
3 Anatomic Pathology, Division of Clinical Laboratory, Miyazaki Prefectural Hospital, Miyazaki,
4 Department of Pathology, Kochi Medical School, Kochi,
5 Clinical Laboratory, Matsuyama-Shimin Hospital, Matsuyama,
6 Department of Pathology, Kamo Hospital, Toyota, Aichi,
7 Department of Laboratory Medicine, Tokushima Central Prefectural Hospital, Tokushima,
8 Department of Pathology, Akita Red Cross Hospital, Akita,
9 Department of Research, Fukui Prefectural Geriatric Center, Fukui,
10 Department of Pathology, Kawasaki Medical School, Kurashiki,
11 Division of Laboratory Research, Iwakuni National Hospital, Iwakuni,
12 Department of Pathology, Nagano Red Cross Hospital, Nagano,
13 Division of Laboratory Pathology, Yaizu Municipal General Hospital, Yaizu,
14 Division of Laboratory Pathology, Urawa Municipal Hospital, Urawa,
15 Department of Pathology, Okayama University Hospital, Okayama,
16 Department of Pathology, Sasebo City General Hospital, Sasebo,
17 Department of Pathology, Yokosuka Kyosai Hospital, Kanagawa,
18 Department of Pathology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors' Hospital, Hiroshima and
19 National Institute of Radiological Sciences, Chiba, Japan
Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as 
-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 -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 -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 -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.
Abbreviations: LET, linear energy transfer; SSCP, single strand conformation polymorphism.
20 Present address: Yasuda Women's University, Hiroshima, Japan
21 To whom correspondence should be addressed Email: iwamoto{at}rerf.or.jp
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  O. Ashur-Fabian, A. Avivi, L. Trakhtenbrot, K. Adamsky, M. Cohen, G. Kajakaro, A. Joel, N. Amariglio, E. Nevo, and G. Rechavi Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation PNAS, August 17, 2004; 101(33): 12236 - 12241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S A Khan, P L Carmichael, S D Taylor-Robinson, N Habib, and H C Thomas DNA adducts, detected by 32P postlabelling, in human cholangiocarcinoma Gut, April 1, 2003; 52(4): 586 - 591. [Abstract] [Full Text] [PDF]
|
|