Irradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival

dc.contributor.authorLaurent, Danny
dc.contributor.authorSmith, Abbi E.
dc.contributor.authorBessler, Waylan K.
dc.contributor.authorMendonca, Marc
dc.contributor.authorChin-Sinex, Helen
dc.contributor.authorDescovich, Martina
dc.contributor.authorHorvai, Andrew E.
dc.contributor.authorClapp, D. Wade
dc.contributor.authorNakamura, Jean L.
dc.contributor.departmentRadiation Oncology, School of Medicineen_US
dc.date.accessioned2022-12-15T17:28:14Z
dc.date.available2022-12-15T17:28:14Z
dc.date.issued2021-04-23
dc.description.abstractBackground: Genetically susceptible individuals can develop malignancies after irradiation of normal tissues. In the context of therapeutic irradiation, it is not known whether irradiating benign neoplasms in susceptible individuals promotes neoplastic transformation and worse clinical outcomes. Individuals with Neurofibromatosis 1 (NF1) are susceptible to both radiation-induced second malignancies and spontaneous progression of plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs). The role of radiotherapy in the treatment of benign neoplasms such as PNs is unclear. Methods: To test whether radiotherapy promotes neoplastic progression of PNs and reduces overall survival, we administered spinal irradiation (SI) to conditional knockout mouse models of NF1-associated PNs in 2 germline contexts: Nf1 fllfl ; PostnCre + and Nf1 fl/- ; PostnCre + . Both genotypes develop extensive Nf1 null spinal PNs, modeling PNs in NF1 patients. A total of 101 mice were randomized to 0 Gy, 15 Gy (3 Gy × 5), or 30 Gy (3 Gy × 10) of spine-focused, fractionated SI and aged until signs of illness. Results: SI decreased survival in both Nf1 fllfl mice and Nf1 fl/- mice, with the worst overall survival occurring in Nf1 fl/- mice receiving 30 Gy. SI was also associated with increasing worrisome histologic features along the PN-MPNST continuum in PNs irradiated to higher radiation doses. Conclusions: This preclinical study provides experimental evidence that irradiation of pre-existing PNs reduces survival and may shift PNs to higher grade neoplasms.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationLaurent D, Smith AE, Bessler WK, et al. Irradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival. Neurooncol Adv. 2021;3(1):vdab063. Published 2021 Apr 23. doi:10.1093/noajnl/vdab063en_US
dc.identifier.urihttps://hdl.handle.net/1805/30754
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.isversionof10.1093/noajnl/vdab063en_US
dc.relation.journalNeuro-Oncology Advancesen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectHeterozygosityen_US
dc.subjectMalignant transformationen_US
dc.subjectNeurofibromatosis Ien_US
dc.subjectPlexiform neurofibromasen_US
dc.subjectRadiationen_US
dc.titleIrradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survivalen_US
dc.typeArticleen_US
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