Focal Fractionated Irradiation Induces Specific Malignancies In A Dose-Dependent Manner In Nf1 Mutant Mice

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Purpose: Secondary malignant neoplasms (SMNs) are a severe late complication of radiotherapy (RT). However little is known regarding the influence of radiation dose or genetic factors on this risk. Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), and clinical observations suggest that affected persons are at increased risk of developing radiation-induced SMNs. NF1 encodes a GTPase activating protein that negatively regulates Ras signaling networks. We administered fractionated cranial irradiation (CI) to heterozygous Nf1 mutant (Nf1+/−) mice in an effort to accurately model common human SMNs. Materials and Methods: 121 C57BL6-Sv129 Nf1+/− and control wild-type (WT) mice were assigned to one of three CI treatment regimens: 0 Gy, 15 Gy (5 daily doses of 3 Gy), or 30 Gy (10 daily doses of 3 Gy). Results: Mice were observed for 18 months after CI or until they developed signs of disease requiring euthanasia. Kaplan-Meier analyses and log-rank tests demonstrate that Nf1 heterozygosity and radiotherapy are independently associated with significantly greater risks of death after CI (p <, respectively). Whereas 15 Gy and 30 Gy CI are associated with similar rates of death in Nf1+/− mice, there was a remarkable difference in the disease spectrum at each dose. Myeloid malignancies were more likely to arise in Nf1+/− mice that received 15 Gy of CI, compared to Nf1+/− mice that received 30 Gy CI or any wildtype mice. By contrast, Nf1+/− mice receiving 30 Gy of CI succumbed to solid tumors such as squamous cell carcinoma (SCC) or sarcomas developing in the radiation field. These radiation-induced tumors arose at a significantly increased incidence in Nf1+/− mice receiving 30 Gy compared to Nf1+/− mice receiving 15 Gy and all wildtype mice. Cultured radiation-induced tumor cells show hyperactive Ras signaling in response to growth factor stimulation, and are sensitive to inhibitors of the mTOR-S6 kinase signaling pathway in vitro. Conclusion: Nf1+/− mice provide a sensitized genetic background for investigating radiation-induced SMNs. Importantly, these mice develop many of the most common SMNs found in human patients. Nf1+/− mice develop predominately hematologic abnormalities at the 15 Gy dose, while solid tumors predominate at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and non-hematologic cancers. Radiation-induced solid tumors display aberrant Ras signaling and are dependent on downstream signaling for survival in culture. The ability to administer focal fractionated radiation to mice will facilitate studies addressing the pathogenesis of common SMNs and for testing preventive and therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3427A.