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

JCI Insight. 2019 Jul 11;4(13):e128698. doi: 10.1172/jci.insight.128698.


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 impact 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 in a novel model combining both factors (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 indel to substitution ratio and amount 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 KrasG12Dp53-/- sarcomas did not harbor recurrent oncogenic mutations, rather they exhibited amplifications of specific oncogenes: Kras and Myc in KrasG12Dp53-/- sarcomas, and Met and Yap1 for radiation-induced sarcomas. These results reveal that different initiating events drive oncogenesis through distinct mechanisms.

Keywords: Cancer; Genetics; Molecular genetics; Oncogenes; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / radiation effects
  • Carcinogens / toxicity
  • DNA Mutational Analysis
  • Exome Sequencing
  • Genomic Instability / radiation effects
  • Humans
  • Methylcholanthrene / toxicity
  • Mice
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Radiation-Induced / genetics*
  • Oncogenes / genetics*
  • Oncogenes / radiation effects
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Sarcoma / chemically induced
  • Sarcoma / genetics*
  • Tumor Suppressor Protein p53 / genetics


  • Carcinogens
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Methylcholanthrene
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)