Li-Fraumeni Syndrome (LFS) is a rare cancer predisposition syndrome, typically involving germline mutations in the TP53 gene. Despite the high penetrance of TP53 mutations, LFS patients display striking phenotypic differences, suggesting the presence of secondary risk loci. To date, all genetic modifiers in LFS have been shown to map to either TP53 or its principal negative regulator, Mdm2. Given this strong association, we set out to interrogate the contribution of a recently-described miRNA regulator of the p53-MDM2 loop, called miR-605. We hypothesized that, if functional, the miR-605 gene and its variant (rs2043556) could impact cancer risk in TP53 mutation carriers. Consistent with this proposition, the variant allele of miR-605 was associated with a significant acceleration in tumor onset and caused a decrease in the processing efficiency of its host miRNA. We also demonstrate that miR-605 overexpression activates the MAPK pathway and leads to tumor suppression in TP53 mutant cell lines.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/44027 |
| Date | 18 March 2014 |
| Creators | Badr, Idsaid |
| Contributors | David, Malkin |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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