title: A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome.
abstract: Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome, typically associated with 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 investigate the contribution of miR-605, a recently described microRNA (miRNA) regulator of the p53-MDM2 loop. We hypothesized that, if functional, the miR-605 gene and its variant (rs2043556) could impact the cancer risk profile of TP53 mutation carriers. Consistent with this proposition, the variant G-allele of miR-605 was associated with a 10-year acceleration in the mean age of LFS tumor onset (P = 0.04) and caused a 2.6-fold reduction in the processing levels of its host miRNA (P < 0.05). We also demonstrate that miR-605 overexpression leads to a decrease in cell proliferation, clonogenicity, and migration in two rhabdomyosarcoma cell lines carrying hotspot TP53 mutations. Together, our results implicate miR-605 as a novel modifier gene of the LFS phenotype and a promising therapeutic target in TP53 mutant cancers.
authors: Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: Badr
authors: B
authors: Id Said
authors: Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. Electronic address: david.malkin@sickkids.ca.
authors: David
authors: D
authors: Malkin
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C556602:MIRN605 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Li-Fraumeni syndrome; MicroRNA; p53; single nucleotide polymorphism