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Volume 8, Issue 6, Pages 1187-1196 (December 2001) Impaired Nonhomologous End-Joining Provokes Soft Tissue Sarcomas Harboring Chromosomal Translocations, Amplifications, and Deletions Norman E. Sharpless, David O. Ferguson, Rónán C. O'Hagan, Diego H. Castrillon, Charles Lee, Paraskevi A. Farazi, Scott Alson, James Fleming, Cynthia C. Morton, Karen Frank, Lynda Chin, Frederick W. Alt, Ronald A. DePinho Molecular Cell Volume 8, Issue 6, Pages 1187-1196 (December 2001) DOI: 10.1016/S1097-2765(01)00425-7

Figure 1 Transformation Assays (A) Giemsa-stained foci at day 10 after transfection with Myc and Ras by the lig4 genotype. (B) Relative foci number of ink4a/arf−/− MEFs by lig4 genotype. ink4a/arf−/− littermate lines (two lig4−/−, five lig4+/−, and five lig4+/+) were transfected with Myc and Ras in five separate experiments. Foci numbers were compared with a paired two-tailed t test. The fold increase relative to lig4+/+ink4a/arf−/− cells is plotted +/− the standard error of the mean (SEM). (C) Myc/Ras foci formation is not decreased by Lig4 reexpression. The results represent an average of two independent Myc/Ras transfections per line, with two or three lines per genotype plotted +/− SEM. (D) Radiosensitivity is rescued by Lig4 expression. The results represent the geometric mean of two independent Myc/Ras-transformed MEF lines per genotype. Molecular Cell 2001 8, 1187-1196DOI: (10.1016/S1097-2765(01)00425-7)

Figure 2 lig4+/−ink4a/arf−/− Mice Demonstrate Increased Radiosensitivity and Accelerated Tumorigenesis (A) Survival analysis after IR treatment. Littermate mice (n = 14–15 per genotype) were irradiated with 6 Gy at 6 weeks of age. KM Curves are compared with the log rank test. (B) Tumor-free survival. lig4+/+ink4a/arf−/− (n = 27) and lig4+/−ink4a/arf−/− (n = 39) mice were followed for the appearance of spontaneous tumors. (C) Tumor histology. Representative sarcomas of the indicated histologic types from lig4+/−ink4a/arf−/− mice are shown with hematoxylin and eosin and the indicated immunohistochemical staining. MPNST stands for malignant peripheral nerve sheath tumor. Molecular Cell 2001 8, 1187-1196DOI: (10.1016/S1097-2765(01)00425-7)

Figure 3 lig4+/−ink4a/arf−/− Tumors Harbor Translocations by Spectral Karyotyping (A) Partial multicolor karyotype of a representative lig4+/−ink4a/arf−/− sarcoma (tumor #10 on Tables 2 and 3; also see Supplemental Data) showing a reciprocal translocation involving chromosomes 9 and 19. (B) SKY findings are confirmed by FISH with chromosome-specific paints for 9 and 19 (Lee et al., 2001). Molecular Cell 2001 8, 1187-1196DOI: (10.1016/S1097-2765(01)00425-7)

Figure 4 lig4+/−ink4a/arf−/− Tumors Demonstrate mdm2 Amplification and Overexpression Southern and Western analysis of mdm2 in 14 representative tumors by lig4 genotype. Approximate amplification (quantified by Southern and slot blot with comparison to a housekeeping gene) is shown for tumors with more than a 2-fold increase. An asterisk indicates a nonspecific crossreactive band. “Gen. DNA” indicates a genomic chromosome 19 probe from a nonamplified region as determined by array-CGH. Molecular Cell 2001 8, 1187-1196DOI: (10.1016/S1097-2765(01)00425-7)