The principal investigator's laboratory has reported a novel type of genetic alteration in cancer, loss of imprinting (LOI). Genomic imprinting is an epigenetic modification of a specific parental chromosome in the gamete or zygote that leads to differential expression of the two alleles of a gen in somatic cells of the offspring. The laboratory has reported genomic imprinting of three human genes: IGF2 (insulin-like growth factor-2) expressed from the paternal allele H19, a growth inhibitory gene expressed from the maternal allele: and p57KIP2, a cyclin-dependent kinase inhibitor also expressed from the maternal allele. Furthermore, they showed that LOI (i.e the loss of parental- origin-specific gene expression) was a common alteration in childhood tumors (e.g.) Wilms tumor), and possibly adult cancer as well, and that LOI is linked to abnormal gene expression in cancer. Finally they identified an imprint-specific chromosomal mark involving cytosine DNA methylation of a CpG island upstream of the H19 gene, and found that this mark is reversed in tumors with LOI.
Specific aims of this proposal are as follows.
Aim 1. The sequence and tempo of loss of imprinting in cancer will be assessed using Wilms tumor as a model of childhood cancer, and colorectal cancer as a model of adult malignancy, Aim 2. Additional genes which show loss of imprinting in cancer will be identified.
Aim 3. A determination will be made whether loss of imprinting is a mechanism for abnormal gene expression and tumor cell proliferation.
Aim 4. The mechanism of loss of imprinting in cancer will be assessed, by precise localization of cis-acting sequences that mediate LOI, and identification of trans-acting factors whose gain or loss mediate abnormal.
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