Carcinogenesis Advance Access originally published online on April 5, 2006
Carcinogenesis 2006 27(9):1860-1866; doi:10.1093/carcin/bgl029
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Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype
1 Department of Molecular Genetics, City of Hope/Beckman Research Institute Duarte, CA 91010, USA
2 Department of Biology, The University of Western Ontario London, Ontario, Canada N6A 5B7
4 Bioinformatics Group, Department of Molecular Genetics City of Hope, Duarte, CA 91010, USA
3 Present address: University of California San Francisco, CA, USA
*To whom correspondence should be addressed at: Department of Molecular Genetics, Beckman Research Institute/City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-0269, USA. Tel: +1 626 930 5497; Fax: +1 626 301 8142; Email: sommerlab{at}coh.org
Mutations are the substrate of cancer. Yet, little is known about the degree and nature of mutations in tumors because measurement of mutation load in tumors and normal tissues was generally not possible until the advent of transgenic mouse mutation detection systems. Herein, we present the first analysis of mutation frequency and pattern in thymic tumors from a mouse model of Li-Fraumeni syndrome (p53+/– murine model) using the Big Blue® assay with sequencing of all mutants. We also make the first characterization of mutation frequency and pattern in p53-deficient extra-thymic cancers. The data more than triple the literature on all non-mismatch repair deficient tumors for which mutations are identified by sequence analysis, allowing mutation frequency and pattern to be determined. Most tumors had a normal mutation frequency and a normal mutation pattern. Five tumors showed modest increases in mutation frequency (2.3-fold or less). Alterations in mutation patterns were uncommon, tumor-specific and not necessarily associated with increases in mutation frequency. Given the data from two spontaneous tumors (normal mutation frequency with an abnormal pattern in a p53–/– mouse and low mutation frequency in a p53+/+ control mouse), we hypothesize that tumors sometimes can carry a low mutation load. The study was not without certain caveats: mutation load could not be compared between tumor and normal tissue from the same animal; sample sizes for extra-thymic tumor types were small, and only point mutations and deletions, insertions and indels up to 2 kb were detected. However, the data clearly show key differences in tumors from p53+/– mice compared with mismatch repair deficient tumors; a lack of dramatic increase in mutation frequency and absence of a signature of mutation.
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  J. Wang, K. D. Gonzalez, W. A. Scaringe, K. Tsai, N. Liu, D. Gu, W. Li, K. A. Hill, and S. S. Sommer From the Cover: Evidence for mutation showers PNAS, May 15, 2007; 104(20): 8403 - 8408. [Abstract] [Full Text] [PDF]
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