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

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alph a-particles from radon, is a current public health issue. The study of tumo rs attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate int ernal exposure to alpha-radiation from thorium dioxide deposits following i ntravascular administration of the radiographic contrast agent Thorotrast i s known to markedly increase the risk of cancer development, especially tha t of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrough t by the high LET alpha-particle, the specific genes and the actual sequenc e of events involved in the process of transforming a normal cell into a ma lignant one are largely unknown. To shed some light on the molecular mechan isms of cancer development during a lifetime exposure to a-radiation, we an alyzed 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 patient s also had p53 mutations? albeit at lower frequency: The distribution patte rn 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 tha t p53 mutations are important in the genesis of Thorotrast-induced tumors b ut that these point mutations are a secondary outcome of genomic instabilit y induced by the irradiation. Additionally, non-tumor cells harboring p53 m utations may gain some survival advantage in situ but mutations in the doma ins responsible for the formation of structural elements critical in bindin g DNA may be necessary for a cell to reach full malignancy.