Wednesday, April 24, 2024
4/24/2024
Abstract Li Fraumeni patients, which harbor heterozygous p53 germ line mutation, are highly predisposed to cancers. The penetrance of these individuals can vary greatly; some individuals have tumor onset prior to age 1, while some individual that do not present with cancer by age 74. P53 is the most widely mutated gene in sporadic cancers, therefore understanding the mechanisms that impact tumor penetrance will have great benefit to pre- dicting individual cancer risk. We have made the unique observation that haploinsufficient Esco2 loss, in both zebrafish and mouse, accelerated tumor formation in a p53 heterozygous animals, but not p53 wild type or homozygous null animal. In addition we observe a high proportion of cells in Esco2 heterozygous null animals to have reduced sister chromatid cohesion (SCC). These observations establish our hypothesis that reduced SCC results in increased rates of loss of heterozygosity, which accelerates the timing of tumor initiation and enhanced tumor penetrance. Within this proposal we will address this hypothesis and decipher the mechanism of how Esco2 loss acts as a penetrance modifier. Aim 1, determine if there are accelerated LOH rates, and the type/s of genomic instability that drive accelerated tumorigenesis, in tumors from animals with reduced cohe- sion; Aim 2, determine if the extent of tumor enhancement is dependent on the extent of cohesion dysfunction; Aim 3, determine if biochemically if reduced acetylation by the cohesion establishment factor, ESCO2 lends to reduced cohesion and tumor enhancement. The expected overall impact of the proposed work is that it will fundamentally advance our mechanistic understanding of a how SCC dysfunction impacts tumorigenesis. This will serve as the foundation for future therapeutic intervention and predictive biomarkers of cancer risk.
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