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

Abstract

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.

• Authors: 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
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 13 (07 11 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31112524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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