title: The MDM2 285G-309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome.
abstract: In the Li-Fraumeni syndrome (LFS) resulting from germline TP53 mutations, the MDM2 SNP309G allele has been shown to be associated with an earlier age of tumour onset, however the significance of this association is controversial. The 285C variation, also located in the MDM2 promoter, has been shown to reduce the strength of Sp1 binding to MDM2 promoter, antagonizing the effect of the 309G variation. In this study, we investigated the interaction of the MDM2 SNP285 and 309 in a large series of 195 LFS patients. Although we observed a lower mean age of tumour onset in patients with MDM2 SNP309 T/G or G/G genotype (23.1 years) than in patients with T/T genotype (27.3 years), the difference was not statistically significant. In contrast, patients with the 285-309 G-G haplotype develop tumours 5 years earlier than patients harbouring other haplotypes (p = 0.044). This result shows that the MDM2 285-309 G-G is a higher risk haplotype in patients with germline TP53 mutations. This study confirms that the MDM2 309G variation is deleterious when its effect is not neutralized by the 285C variation and illustrates the interfering effects of SNPs located within a gene acting as modifier factor in a Mendelian disease.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, 76183, Rouen, France.
authors.forename: Mariette
authors.initials: M
authors.lastname: Renaux-Petel
authors.forename: Richard
authors.initials: R
authors.lastname: Sesboüé
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baert-Desurmont
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Vasseur
authors.forename: Steeve
authors.initials: S
authors.lastname: Fourneaux
authors.forename: Emilie
authors.initials: E
authors.lastname: Bessenay
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bougeard
mesh_terms: D000328:Adult; D017668:Age of Onset; D005260:Female; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2