Carcinogenesis Advance Access first published online on April 5, 2006
This version published online on May 18, 2006
Carcinogenesis, doi:10.1093/carcin/bgl029
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1 Department of Molecular Genetics, City of Hope/Beckman Research Institute, Duarte, CA 91010; Department of Biology, The University of Western Ontario, London Ontario, Canada N6A 5B7
* To whom correspondence should be addressed. 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) and 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 at p53-/- mouse and low mutation frequency in a p53+/+ control mouse), we hypothesize that the 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 to mismatch repair deficient tumors: a lack of dramatic increase in mutation frequency and absence of a signature of mutation.
Received December 16, 2005
Revised March 21, 2006
Accepted March 22, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype
Kathleen A. Hill 1,
Victoria L. Buettner 2,
Annaleah Heidt 3,
Wenyan Li 2,
Kelly D. Gonzalez 2,
Ji-Cheng Wang 2,
Linling Chen 2,
William A. Scaringe 4,
and
Steve S. Sommer 2 *
2 Department of Molecular Genetics, City of Hope/Beckman Research Institute, Duarte, CA 91010
3 Department of Molecular Genetics, City of Hope/Beckman Research Institute, Duarte, CA 91010; Current Address: University of California San Francisco
4 Department of Molecular Genetics, City of Hope/Beckman Research Institute, Duarte, CA 91010; Bioinformatics Group, Department of Molecular Genetics, City of Hope, Duarte, CA 91010
Steve S. Sommer, E-mail: sommerlab{at}coh.org
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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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