Mutational Analysis of Ionizing Radiation Induced Neoplasms

Area of Science:

• Oncology
• Genetics
• Radiation Biology

Background:

• Ionizing radiation (IR) is a known mutagen that can lead to tumorigenesis.
• Second malignant neoplasms (SMNs) are a serious complication of radiotherapy, particularly in pediatric cancer survivors.
• The genomic landscape of SMNs and the impact of genetic background on genotoxin-induced mutations remain underexplored.

Purpose of the Study:

• To characterize the genomes of radiation-induced second malignant neoplasms (SMNs).
• To investigate the influence of genetic background on the mutational landscape induced by ionizing radiation.
• To identify mutational signatures and genomic alterations in a mouse model of SMNs.

Main Methods:

• Whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice.
• Non-negative matrix factorization to identify mutational signatures.
• Copy-number analysis and pathway analysis to detect chromosomal alterations and variant enrichment.

Main Results:

• Mutational signatures did not segregate by genetic background or tumor histology.
• Copy-number analysis revealed recurrent chromosomal alterations, with background-dependent differences.
• Enrichment of variants was observed in genes involved in cell assembly, organization, morphology, and maintenance.
• Ionizing radiation and Nf1 heterozygosity independently influenced the mutational landscape.

Conclusions:

• The study provides a comprehensive genomic characterization of radiation-induced SMNs in a mouse model.
• Genetic background plays a role in copy-number alterations but not in mutational signatures.
• Both ionizing radiation and genetic factors like Nf1 heterozygosity contribute distinct patterns to the tumor mutational landscape.