Li Fraumeni Syndrome (LFS) is an autosomal recessive disorder characterized by early age of onset of carcinomas and soft tissues sarcomas. Individuals with LFS most often inherit missense mutations in the p53 tumor suppressor gene. Chromosomal instability is a hallmark of human carcinomas, and tumors derived from individuals with LFS often contain a multitude of aberrant chromosomes. Increasing evidence from human and mouse model systems suggests that proper maintenance of telomeres is important for chromosomal integrity and genome stability. Telomere dysfunction initiates the formation of the breakage-fusion-bridge cycle, leading to genome-wide alterations in gene dosage. In the setting of mutant p53, these diverge genetic alterations are demonstrated to fuel cancer initiation and progression. Mouse models of human cancers normally have very long telomeres, thus masking the contributions that critically short telomeres may play on cancer initiation and progression. To test the hypothesis that telomere dysfunction promotes chromosomal instability and accelerates the onset of tumorigenesis in vivo in the setting of the most common gain-of-function mutation in human LFS (the p53R172H mutation), I have generated mice with normal or dysfunctional telomeres heterozygous or homozygous for the p53R172H mutation. I will compare the latency of tumor development, tumor spectrum, types of chromosomal aberrations observed, and telomere length of spontaneous and carcinogen induced tumors and derivative tumor cell lines between these mouse cohorts.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM075682-01
Application #
6994137
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2005-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$29,063
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030