Mutational Analysis of Ionizing Radiation Induced Neoplasms.

Cell Reports
Amy L SherborneJean L Nakamura

Abstract

Ionizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape.

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Citations

Dec 14, 2016·Histopathology·Lynette M ShollJason L Hornick
Mar 28, 2017·Mutation Research. Reviews in Mutation Research·Janet HallElisabeth Cardis
Jan 18, 2017·Future Oncology·Tomer CharasMichael J Zelefsky
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Dec 10, 2019·Journal of Pediatric Hematology/oncology·Vincent LavergneJean L Nakamura
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Jul 9, 2020·Nature Reviews. Cancer·Julia WeberRoland Rad
Sep 30, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Amy L SherborneJean L Nakamura

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