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.

Numerous reports have highlighted the contribution of MSH2 and MLH1 genomic deletions to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch's syndrome, but genomic duplications of these genes have been rarely reported. Using quantitative multiplex PCR of short fluorescent fragments (QMPSF), 962 and 611 index cases were, respectively, screened for MSH2 and MLH1 genomic rearrangements. This allowed us to detect, in 11 families, seven MSH2 duplications affecting exons 1-2-3, exons 4-5-6, exon 7, exons 7-8, exons 9-10, exon 11, and exon 15, and three MLH1 duplications affecting exons 2-3, exon 4 and exons 6-7-8. All duplications were confirmed by an independent method. The contribution of genomic duplications of MSH2 and MLH1 to HNPCC can therefore be estimated approximately to 1% of the HNPCC cases. Although this frequency is much lower than that of genomic deletions, the presence of MSH2 or MLH1 genomic duplications should be considered in HNPCC families without detectable point mutations.