Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma
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
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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Research Article Genetics Oncology

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 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.

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

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Figure 1

Somatic mutation analysis of murine soft-tissue sarcomas.

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Somatic mutation analysis of murine soft-tissue sarcomas. (A) Schematics...
(A) Schematics of the methods to generate various mouse models of soft-tissue sarcomas: IR-induced (blue), MCA-induced p53 WT (red), MCA-induced p53–/– (green), and KrasG12D p53–/– sarcomas (purple). (B) The number of total somatic mutations per tumor. (C) The number of somatic nonsynonymous mutations per tumor. (D) The proportion of insertions-deletions (indels) within nonsynonymous mutations. IR-induced sarcomas showed a higher median proportion of nonsynonymous mutations that were indels (P = 0.0003). (E) The proportion of insertions or deletions within nonsynonymous mutations. (F) The proportions of different single-nucleotide substitutions. IR-induced sarcomas exhibited higher C-to-T (P = 0.0002) and G-to-A (P = 0.0006) transitions. (G) Unsupervised hierarchical clustering of sarcomas based on data of single-nucleotide substitutions. P values were calculated by the Kruskal-Wallis test. B–G illustrate the data for n = 37 tumors. The box plots in D–F depict the minimum and maximum values or a length of 1.5 times the interquartile range (whichever was shorter; whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range.