Mutational landscape in genetically engineered, carcinogen-induced, and radiation-associated mouse models of sarcoma

Cancer development can be influenced by hereditary mutations, somatic mutations due to random errors in DNA replication, and environmental factors such as chemical carcinogens and ionizing radiation. However, it remains unclear how distinct cell-intrinsic and -extrinsic factors impact cancer development within the same tissue type. Here, we investigated this question in murine soft tissue sarcomas generated through genetic or environmental insults including oncogenic alterations (KrasG12D activation and p53 deletion), carcinogens (methylcholanthrene [MCA] or ionizing radiation), and a novel model combining both factors (MCA plus p53 deletion). Whole exome sequencing demonstrated distinct mutational signatures for these individual sarcoma cohorts. MCA-induced sarcomas exhibited high mutational burden and predominantly cytosine to adenine transversions. In contrast, radiation-induced sarcomas typically exhibited low mutational burden and a distinct genetic signature characterized by cytosine to thymine transitions. The indel to substitution ratio was significantly higher for radiation-induced sarcomas, which also had more genes affected by copy number variations (CNVs) than MCA-induced tumors generated on a p53 wild type background. On the other hand, MCA-induced tumors generated on a p53-deficient background showed the highest genomic instability demonstrated by high CNVs and high mutational burden. Analysis of gene mutations indicated that MCA-induced sarcomas harbored mutations in putative cancer-driver genes that regulate MAP-Kinase signaling (Kras and NF1) and the Hippo pathway (FAT1 and FAT4). In contrast, radiation-induced sarcomas and KrasG12D; p53-/- sarcomas did not harbor any recurrent oncogenic mutations, but they exhibited amplifications of specific oncogenes: Kras and Myc amplifications in KrasG12D; p53-/- sarcomas, as well as Met and Yap1 amplifications for radiation-induced sarcomas. Together, these results reveal that oncogenic alterations, chemical carcinogens, and ionizing radiation induce tumors by altering critical oncogenic pathways through distinct mechanisms.