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Updated: May 17, 2026
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Published on: May 17, 2024
Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms
Grace Choi1, Brian Huang, Emile Pinarbasi
1Department of Radiation Oncology, University of California, San Francisco, San Francisco, California, USA.
Abstract:
Second malignant neoplasms (SMN) are therapy-induced malignancies and a growing problem in cancer survivors, particularly survivors of childhood cancers. The lack of experimental models of SMNs has limited understanding of their pathogenesis. It is currently not possible to predict or prevent this devastating late complication. Individuals with neurofibromatosis I (NF1) are at increased risk of developing therapy-induced cancers for unclear reasons. To model SMNs, we replicated clinical radiotherapy and delivered fractionated abdominal irradiation to Nf1(+/-) and wild-type mice. Similar to irradiated cancer survivors, irradiated wild-type and Nf1(+/-) mice developed diverse in-field malignancies. In Nf1(+/-) mice, fractionated irradiation promoted both classical NF1-associated malignancies and malignancies unassociated with the NF1 syndrome but typical of SMNs. Nf1 heterozygosity potentiated the mutagenic effects of irradiation, as evidenced by the significantly reduced survival after irradiation and tumor development that was often characterized by synchronous primary tumors. Interestingly, diverse radiation-induced tumors arising in wild-type and Nf1(+/-) mice shared a genetic signature characterized by monoallelic loss of Nf1 and the adjacent Trp53 allele. These findings implicate Nf1 loss as mediating tumorigenesis in a broad range of cell types and organs extending beyond the classical NF1 tumor histologies. Examining clinical SMN samples, we found LOH of NF1 in SMNs from non-NF1 patients. Nf1 heterozygosity confers broad susceptibility to genotoxin-induced tumorigenesis, and this paradigm serves as an experimental platform for future studies of SMNs.
Insights
Second malignant neoplasms (SMNs) are a growing concern in cancer survivors. This study reveals that neurofibromatosis I (NF1) gene loss enhances susceptibility to radiation-induced tumors, offering a new model for SMN research.
Area of Science:
- Oncology
- Cancer Genetics
- Radiation Biology
Background:
- Second malignant neoplasms (SMNs) are therapy-induced cancers in survivors, posing a significant clinical challenge.
- Lack of experimental models hinders understanding of SMN pathogenesis and prevention.
- Individuals with neurofibromatosis I (NF1) exhibit increased risk for therapy-induced cancers, with underlying mechanisms unclear.
Purpose of the Study:
- To develop and utilize an experimental model for studying the pathogenesis of SMNs.
- To investigate the role of NF1 heterozygosity in susceptibility to radiation-induced tumorigenesis.
- To identify shared genetic alterations in radiation-induced tumors.
Main Methods:
- Fractionated abdominal irradiation was administered to wild-type and Nf1(+/-) mice to model clinical radiotherapy.
- Tumor development, survival rates, and genetic profiles of irradiated mice were analyzed.
- Clinical samples of SMNs from non-NF1 patients were examined for NF1 alterations.
Main Results:
- Irradiated wild-type and Nf1(+/-) mice developed diverse in-field malignancies, mimicking human SMNs.
- Nf1 heterozygosity potentiated radiation's mutagenic effects, leading to reduced survival and synchronous tumors.
- Radiation-induced tumors in both genotypes shared a genetic signature of monoallelic loss of Nf1 and Trp53.
- Loss of heterozygosity (LOH) for NF1 was observed in SMNs from non-NF1 patients.
Conclusions:
- NF1 loss mediates tumorigenesis across various cell types and organs, extending beyond classical NF1-associated tumors.
- NF1 heterozygosity confers broad susceptibility to genotoxin-induced tumorigenesis.
- This preclinical model provides a platform for future SMN research and the development of preventative strategies.
