The overall goal of the project is to determine how loss of imprinting (LOI) of IGF2, a growth factor, affects the development of colorectal cancer (CRC). Loss of imprinting refers to the epigenetic phenomenon where a normally monoallelically expressed gene (expressed from paternal or maternal copy only) becomes biallelically expressed. In the case of LOI, which occurs in 5-10% of the US population, this has been found to increase the probability of developing CRC as much as 5 times.
Specific Aim 1 : Determine the interaction between LOI affected (IGF2) and CRC controlling (Wnt/3-catenin) pathways using immunofluorescence and fluorescent protein fusions to gather high content data, on fibroblasts derived from our model mice and CRC cell lines.
Specific Aim 2 : Further characterize the differences between our model mice, paying special attention to differences occurring in the colonic crypts, to determine the changes in the balance of growth, differentiation and apoptosis;and in blood to determine possible targets for easier screening of LOI.
Specific Aim 3 : Determine if LOI shifts the type of mutations acquired by CRC by typing banked samples for LOI, then assaying to determine the type and location of their mutations in various gatekeeper genes. A greater understanding of the mechanisms and predispositions that the general population may have towards colorectal cancer is essential. Not only does this aid in developing new methods for screening, it gives the potential to develop tailored, personal therapies to the exact kind of cancer that an individual has, which should prove more effective than broad-spectrum chemotherapies.
|Hansen, Kasper Daniel; Timp, Winston; Bravo, Hector Corrada et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43:768-75|