MDM2 and TP53 are modifier genes of retinoblastoma

Current evidence support the role of DNA repair and apoptosis gene polymorphisms as cancer modifiers. Two common SNPs TP53 R72P and MDM2 SNP309 with known functional effects have been studied with contrasting findings in both sporadic cancer (gastric, lung, childhood ALL) and the inherited Lynch syndrome, and in Li-Fraumeni syndrome a significant interaction between the germline TP53 mutation and the MDM2 SNP has been shown. To investigate their role in hereditary retinoblastoma we genotyped the two SNPs by Pyrosequencing ® assays on blood DNA of 90 patients with known germinal RB1 mutation, 34 familiar. A descriptive analysis showed an earlier age at diagnosis in patients with bilateral retinoblastoma than in those with unilateral retinoblastoma (median age: 0.57 yrs vs 1.49 yrs, respectively, p<0.001). Since age of onset is often nor exactly known, we considered bilaterality as a more robust measure of the variable genetic risk. A multivariate logistic regression model adjusted for age and gender showed the risk of bilateral disease to be: i) as for the type of RB1 mutation higher for splicing and missense mutations than for deletions, duplications, nonsense and frameshift mutations but not significantly so (OR=1.33; 95% CI 0.22 - 8.22); ii) as for the MDM2 SNP309, significantly higher for the GG genotype than TT (OR=11.78, 95% CI 2.18 - 63.65) but not significantly for TG; iii) as for the TP53 R72P SNP not significantly for the PP genotype. Our results suggest for the first time that MDM2 and TP53 may be modifiers of Retinoblastoma as well.