Analysis of TP53 Arg72Pro and MDM2 SNP309 T>G polymorphisms as modifier factors in hereditary retinoblastoma

Retinoblastoma (RB) is the most common primary intraocular malignancy in children, arising by two-hit inactivation of the RB1 gene.Hyper-expression of negative p53 regulators was recently found as a frequent somatic event. Most RB1 mutation carriers develop multifocal RB. However, they show a broad range of phenotypic variability (age of onset, involvement of one/two eyes and needed therapy). To test the hypothesis that this may in part results from variable function of genes involved in cell cycle and apoptosis, we investigated the effect of two functional polymorphisms, one in TP53 (Arg72Pro) and the other in the promoter of MDM2 (SNP309 T>G), on the age of tumour diagnosis. The TP53 Pro allele has been shown to have a weaker proapoptotic activity and to influence age of onset in Lynch syndrome; the MDM2 309G allele to accelerate tumour formation in Li-Fraumeni syndrome and sporadic cancers. We tailored specific Pyrosequencing (C) assays for the two SNPs and genotyped 43 RB patients with a characterized for suspected RB1 germline mutation (i.e. familial and bilateral cases). At univariate analysis, neither the MDM2 nor the TP53 SNP did reveal significant differences on RB onset. We then evaluated their combined effect through modelling estimates. Patients with the GGProPro genotype showed an earlier tumour onset compared to those with GG-ArgArg or GG-ArgPro. An increased number of patients is needed to firmly establish this association. This approach could help in better characterizing the role of the p53 pathway in RB carcinogenesis, and defining more accurate prognosis for patients.