Ionizing radiation (IR) is both a potent mutagen and an important forms of cancer therapy. While its mechanism of action is not clearly elucidated, IR is thought to act by inducing DNA damage through a combination of direct (double-strand breaks) and indirect mechanisms (oxidative stress) and its relative potency is related to the function of tumor suppressors, particularly Trp53. To explorethe impact of IR on the evolution and landscape of the cancer genome and the impact of Trp53 deficiency, we subjected two mouse models of Trp53 dysfunction (n=214): heterozygous loss (het) and homozygous delta proline region deletion (delP) to either a single 50cGy dose of gamma or high-LET (Fe-ion) radiation. We employed whole genome (WGS) and/or exome sequencing (WES) to examine over 75 IR-related tumors and identified characteristics specific to IR quality, Trp53 genotype, and tumor histology/site. Transcriptome sequencing was carried to validate functional gene upregulation. Fe-ion IR was a potent inducer of mammary tumors than gamma IR and resulted in earlier tumor-specific death (multivariate HR=2.36, P<1.9e-06). Fe-ion IR is strongly associated with large focal deletions and structural rearrangements, supporting a mechanism of direct DNA damage. Overall, there is a preponderance of mammary tumors (51/160 animals). There was a strong deletion bias in mammary tumors (52%) as compared to lymphoma (21%) or skin tumors (15%) (p<2.9e0-3).Trp53 delP animals were much more likely to develop carcinomas in the skin, mammary gland, and other tissues, versus other histologic subtypes, (P<3.6e-05). In contrast, animals with Trp53 het genotype were enriched for non-focal rearrangements and aneuploidy compared to mice with the delP allele (P-adjusted<0.01 for deletions and inversions). Examining global SNV and INDEL variants identified both known and novel mutation signatures, including SNV signature 18, which has been associated with inflammation and implicated in oxidative stress. ROS signature 18 was enriched in tumors induced by gamma vs Fe-ion IR (p<0.032). In addition, in a subset of samples, we identified a de novo SNV and INDEL signature strongly attributed to focal regions of high mutation rate, resembling a phenomenon of “focal” chromothripsis. Finally, we identified somatic mutations in well-known driver genes including Kras, Apc, and Trp53. A preponderance of focal Met amplifications were observed in mammary tumors, particularly in animals exposed to Fe-ion vs gamma IR (19 versus 4 sequenced tumors). The functional impact of MET amplification were confirmed by RNA-seq analysis showing over 10-100+ fold expression increase. Our study provides compelling evidence in support of both a role for direct and indirect DNA damage, identifies focal and whole chromosomal chromothripsis, and illustrates complex interaction of Trp53 deficiency and radiation quality in the landscape of IR-mediated tumors.