Mutational Analysis of Ionizing Radiation Induced Neoplasms.
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.
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94158, USA.
Amy L
AL
Sherborne
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Philip R
PR
Davidson
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94158, USA.
Katharine
K
Yu
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Alice O
AO
Nakamura
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Mamunur
M
Rashid
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jean.nakamura@ucsf.edu.
Jean L
JL
Nakamura
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004195:Disease Models, Animal; D018628:Gene Dosage; D016514:Genes, Neurofibromatosis 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011839:Radiation, Ionizing