Cancer development is influenced by hereditary mutations, somatic mutations due to random errors in DNA replication, or external factors. It remains unclear how distinct cell-intrinsic and -extrinsic factors affect oncogenesis within the same tissue type. We investigated murine soft-tissue sarcomas generated by oncogenic alterations (KrasG12D activation and p53 deletion), carcinogens (3-methylcholanthrene [MCA] or ionizing radiation), and both factors in a potentially novel model (MCA plus p53 deletion). Whole-exome sequencing demonstrated distinct mutational signatures in individual sarcoma cohorts. MCA-induced sarcomas exhibited high mutational burden and predominantly G-to-T transversions, while radiation-induced sarcomas exhibited low mutational burden and a distinct genetic signature characterized by C-to-T transitions. The insertion-deletion/substitution ratio and number of gene copy number variations were high for radiation-induced sarcomas. MCA-induced tumors generated on a p53-deficient background showed the highest genomic instability. MCA-induced sarcomas harbored mutations in putative cancer driver genes that regulate MAPK signaling (Kras and Nf1) and the Hippo pathway (Fat1 and Fat4). In contrast, radiation-induced sarcomas and KrasG12D p53–/– sarcomas did not harbor recurrent oncogenic mutations; rather, they exhibited amplifications of specific oncogenes: Kras and Myc in KrasG12D p53–/– sarcomas and Met and Yap1 for radiation-induced sarcomas. These results reveal that different initiating events drive oncogenesis through distinct mechanisms.


Chang-Lung Lee, Yvonne M. Mowery, Andrea R. Daniel, Dadong Zhang, Alexander B. Sibley, Joe R. Delaney, Amy J. Wisdom, Xiaodi Qin, Xi Wang, Isibel Caraballo, Jeremy Gresham, Lixia Luo, David Van Mater, Kouros Owzar, David G. Kirsch


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