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Somatic inactivation of the  TP53  gene in breast tumors is a marker for poor outcome, and breast cancer outcome might also be affected by germ-line variation in the  TP53  gene or its regulators. We investigated the effects of the germ-line single nucleotide polymorphisms  TP53  R72P (215G>C) and  MDM2  SNP309 (-410T>G), and p53 protein expression in breast tumors on survival.    Methods  We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both  TP53  R72P and  MDM2  SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models.    Results  Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1),  P  = 0.001. Within the patient group with p53-negative tumors,  TP53  rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%,  P  = 0.07; HR 1.8 (1.1 to 3.1),  P  = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in  MDM2  had worse survival only within the group of  TP53  C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%,  P  = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0),  P  = 0.01. We found no evidence for a differential effect of  MDM2  SNP309 by p53 protein expression on survival.    Conclusions  The  TP53  R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of  TP53  R72P and  MDM2  SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the  TP53  Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.

Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients