Radiation Risk Prediction and Genetics: The Influence of the TP53 Gene in vivo

Abstract

ᮀ Risk prediction and dose limits for human radiation exposure are based on the assumption that risk is proportional to total dose. However, there is concern about the appropriateness of those limits for people who may be genetically cancer prone. The TP53 gene product functions in regulatory pathways for DNA repair, cell cycle checkpoints and apoptosis, processes critical in determining ionizing radiation risk for both carcinogenesis and teratogenesis. Mice that are deficient in TP53 function are cancer prone. This review examines the influence of variations in TP53 gene activity on cancer and teratogenic risk in mice exposed to radiation in vivo, and compares those observations to the assumptions and predictions of radiation risk inherent in the existing system of radiation protection. Current assumptions concerning a linear response with dose, dose additivity, lack of thresholds and dose rate reduction factors all appear incorrect at low doses. TP53 functional variations can further modify radiation risk from either high or low doses, or risk from radiation exposures combined with other stresses, and those modifications can result in both quantitative and qualitative changes in risk.

Sparsely Ionizing Diagnostic and Natural Background Radiations are Likely Preventing Cancer and other Genomic-Instability-Associated Diseases

“…• Extend tumor latency in cancer-prone mice (Mitchel et al 2003;Mitchel 2004Mitchel , 2005 • Activate the immune response (Liu et al 1987;Makinodan and James 1990;Sakamoto et al 1997;Liu 2003Liu , 2004 and suppress lung and lymph node metastasis in vivo (Hosoi and Sakamoto 1993;Hashimoto et al 1999;Sakamoto 2004). • Suppress spontaneous cancers in humans (Howe, 1995;Rossi and Zaider 1997;Scott 2005aScott , 2006a).…”

Molecular Characterization ofTP53Gene in Human Populations Exposed to Low-Dose Ionizing Radiation

“…Nonmutated p53 normally responds to radiation with a high level of expression and subsequently mediates cell cycle arrest and DNA repair activation [51]. Therefore, this protein is important for monitoring radiosensitivity to both high and low doses of radiation, alone or in combination with other stressors [52]. …”

Physical, Heritable and Age-Related Factors as Modifiers of Radiation Cancer Risk in Patched Heterozygous Mice

“…Thus, although Ptc1-associated BCC and medulloblastoma show common features (i.e., both are radiogenic tumors developing through early preneoplastic lesions that require biallelic Ptc1 loss for progression to full malignancy) (6, 13), skin and cerebellum show markedly different radiosensitivity to tumor induction. The basic concept that individual tissues differ in quantitative response to radiation also emerges in a study on cancer-prone TP53 heterozygous mice in which a single exposure to 100 mGy of X-rays decreased risk of lymphoma by extending tumor latency but increased risk of osteosarcoma (15).…”