MDM2 – Li-Fraumeni syndrome

MDM2 polymorphism SNP309 (c.14+309T>G) acts as a genetic modifier in Li-Fraumeni syndrome (LFS), advancing tumor onset in TP53 germline mutation carriers under an autosomal dominant model. In a combined Dutch (n=25) and Finnish (n=11) cohort of 36 TP53 mutation carriers, G-allele carriers developed cancers at a mean age of 29.7 versus 45.5 years in T/T homozygotes (P=0.005) (PMID:17003841). A French series of 61 TP53 carriers replicated earlier onset in G-allele carriers (19.6 vs 29.9 years; P<0.05) (PMID:16258005). Among 72 TP53-negative LFS-like individuals, G/G homozygotes were significantly overrepresented compared to population controls (P=0.02) (PMID:17003841). Furthermore, in 195 TP53-mutant patients, the MDM2 285-309 G-G haplotype correlated with a 5-year earlier onset relative to other haplotypes (P=0.044) (PMID:23884452). No rare, segregating MDM2 coding variants have been reported.

Functional studies delineate that SNP309 enhances Sp1 transcription factor binding to the MDM2 promoter, elevating MDM2 mRNA and protein, which in turn ubiquitinates and degrades p53. In vitro ubiquitination assays confirm that MDM2 requires p53 oligomerization for efficient ubiquitination, and binding studies identify critical residues for this interaction (PMID:10347217; PMID:8289798). These findings support a mechanism of hyperactive MDM2-mediated p53 attenuation that concords with the modifier effect observed clinically.

MDM2 SNP309 receives a Limited gene–disease association rating as a modifier locus in LFS, with limited genetic evidence from cohort studies and moderate functional support. Testing of this polymorphism may guide personalized surveillance strategies in TP53 mutation carriers but lacks standalone diagnostic validity.

References

• European journal of human genetics : EJHG • 2007 • The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. PMID:17003841
• Journal of medical genetics • 2006 • Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. PMID:16258005
• Familial cancer • 2014 • The MDM2 285G-309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome. PMID:23884452
• Molecular and cellular biology • 1994 • Physical and functional interaction between wild-type p53 and mdm2 proteins. PMID:8289798
• The Journal of biological chemistry • 1999 • Oligomerisation is required for p53 to be efficiently ubiquitinated by MDM2. PMID:10347217

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