Effects of MDM2, MDM4and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations

Abstract

Background: Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied. Methodology/Principal Findings: We analyzed 213 p53 germline mutation carriers including 168(78.9%) affected with cancer and 174 who had genotypic data. We analyzed time to first cancer using Kaplan-Meier and Cox proportional hazards methods, comparing risks according to polymorphism genotypes. For MDM2 SNP309, a significant difference of 9.0 years in the average age of cancer diagnosis was observed between GG/GT and TT carriers (18.6 versus 27.6 years, P =0.0087). The hazards ratio was 1.58 (P=0.03) comparing risks among individuals with GG/GT to risk among TT, but this effect was only significant in females (HR=1.60, P=0.02). Compared to other genotypes, P53 codon 72 PP homozygotes had a 2.24 times (P=0.03) higher rate for time to develop cancer. We observed a multiplicative joint effect of MDM2 and p53 codon72 polymorphism on risk. The MDM4 polymorphism had no significant effects. Conclusions/Significance: Our results suggest that the MDM2 SNP309 G allele is associated with cancer risk in p53 germline mutation carriers and accelerates time to cancer onset with a pronounced effect in females. A multiplicative joint effect exists between the MDM2 SNP309 G allele and the p53 codon 72 G allele in the risk of cancer development. Our results further define cancer risk in carriers of germline p53 mutations. © 2010 Fang et al.