We propose to use a mouse model to investigate genetic modifiers that influence tumorigenesis and embryonic development. In Li-Fraumeni Syndrome (LFS), individuals who inherit a mutant p53 allele are predisposed to tumors with high penetrance. However, the age of onset and the tumor types vary widely in these LFS patients suggesting genetic modifiers at loci other than p53. Inbred CE/J mice, which succumb to multiple types of tumors similar to LFS, were crossed with the p53-null 129/Sv mouse. By this cross, we have uncovered a genetic modifier of p53 that results in embryonic lethality. By genome-wide chromosomal mapping analyses, we identified loci containing modifiers of p53, mop1 and mop2, centromeric and telomeric to p53 on mouse chromosome 11 that causes embryonic lethality when combined with a p53 null allele. To identify the genes encoded by mop1 and mop2, we plan to use chromosomal mapping of embryonic DNA and sequence analysis. We also plan to determine the cause of embryonic death using histological methods. Survivors of these crosses have a more aggressive tumor phenotype, such as earlier onset of tumors and metastasis. By genetic mapping in tumor DNA from these mice, we have narrowed a region to 1 cM that contains a putative tumor suppressor gene. We will sequence candidate genes within this region for mutations in the CE/J strain. The results of this proposed study will provide insight as to the variability in the cancer phenotype in the human disease and lead to the identification of genes whose genetic role with p53 is important during embryonic development and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA112639-01
Application #
6878411
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (O1))
Program Officer
Mietz, Judy
Project Start
2004-09-22
Project End
2006-08-31
Budget Start
2004-09-22
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$73,500
Indirect Cost
Name
Ohio University Athens
Department
Type
Other Domestic Higher Education
DUNS #
041077983
City
Athens
State
OH
Country
United States
Zip Code
45701
Liang, Min; Ayanga, Bernard; Du, Shuhua et al. (2008) Ovca1, a candidate gene of the genetic modifier of Tp53, Mop2, affects mouse embryonic lethality. Genes Chromosomes Cancer 47:315-25