1. Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models
- Author
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Zhaohui Feng, Hua Ke, Chang S. Chan, Yvonne Sun, Yuhan Zhao, Merzu Belete, Arnold J. Levine, Wenwei Hu, and Cen Zhang
- Subjects
Male ,0301 basic medicine ,Heterozygote ,endocrine system diseases ,Carcinogenesis ,Health, Toxicology and Mutagenesis ,Mutant ,Mice, Transgenic ,Plant Science ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Li-Fraumeni Syndrome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Mice, Inbred NOD ,medicine ,Animals ,Genetic Predisposition to Disease ,Epigenetics ,Li fraumeni ,neoplasms ,Gene ,Germ-Line Mutation ,Research Articles ,Mice, Inbred BALB C ,Stochastic Processes ,Ecology ,Cancer ,medicine.disease ,Phenotype ,Penetrance ,Tumor formation ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Mice, Inbred DBA ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Tumor Suppressor Protein p53 ,Research Article - Abstract
This study used mice heterozygous for Tp53 mutations with different genetic backgrounds to investigate the genetic or stochastic factors that modify the penetrance of tumor formation by Tp53 mutation., p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying Tp53 mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.
- Published
- 2020