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

Abstract

Introduction: 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.

Figure 1

Cumulative breast cancer-specific survival (Kaplan Meier) of breast cancer patients with p53 negative tumors stratified by TP53 R72P. Survival in the TP53 CC group was worse compared to that in the GC and GG group combined (80% versus 71%, P = 0.07).

Figure 2

Cumulative overall survival of breast cancer patients by MDM2 SNP309 and TP53 R72P genotypes. Each figure shows Kaplan Meier survival curves of MDM2 SNP309 genotypes within one group of TP53 R72P genotype. (a) TP53 GG genotype (ns); (b) TP53 GC genotype (P = 0.006); (c) TP53 CC genotype (ns). The numbers at start of follow-up were: Figure A: TT n = 798, TG n = 939, GG n = 281; B: TT n = 545, TG n = 698, GG n = 200; C: TT n = 110, TG n = 144, GG n = 25. Within the TP53 C-allele carriers (Figure A and B combined), MDM2 GG carriers had significantly worse survival compared to TT/TG carriers combined: 64% versus 75%, P = 0.001.