MDM2 as a modifier gene in retinoblastoma.

Variability in the age of onset and number of tumors is occasionally described among retinoblastoma patients, and possible genetic modifiers might lie in the pRB or p53 pathways, both of which are involved in the development of retinoblastoma. MDM2, which increases p53 and pRB catabolism, is therefore a prominent candidate. The minor allele of MDM2 that includes a 309T>G transversion (single-nucleotide polymorphism rs2279744) in the MDM2 promoter is known to enhance MDM2 expression. Its genetic transmission was studied in 326 individuals including 212 RB1 mutation carriers in 70 retinoblastoma families, and the marker genotype was tested for association with age at diagnosis and disease phenotype. In family-based association analyses, the MDM2 309G allele was found to be statistically significantly associated with incidence of bilateral or unilateral retinoblastoma among members of retinoblastoma families (Z = 3.305, two-sided exact P = .001) under a recessive model (ie, affected patients tend to be homozygous for the G allele); in transmission disequilibrium analyses using the recessive model, the association was also observed (estimated odds ratio = 4.0, 95% confidence interval = 1.3 to 12.0). The strong association of this genotype with retinoblastoma development designates MDM2 as the first modifier gene to be identified among retinoblastoma patients and suggests that enhancement of pRB haploinsufficiency and/or resistance to p53-mediated apoptosis is critical to tumor formation.