The Pro allele of the p53 codon 72 polymorphism is associated with decreased intratumoral expression of BAX and p21, and increased breast cancer risk

• Published in: PloS one 2012-10, Vol.7 (10), p.e47325-e47325
• Main Authors: Proestling, Katharina, Hebar, Alexandra, Pruckner, Nina, Marton, Erika, Vinatzer, Ursula, Schreiber, Martin
• Format: Article
• Language: English
• Subjects: Alleles; Apoptosis; bcl-2-Associated X Protein - metabolism; Biology; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell cycle; Chemotherapy; Codons; Confidence intervals; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Deactivation; Deoxyribonucleic acid; Development and progression; DNA; DNA repair; Epidemiology; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Gene polymorphism; Genes; Genetic aspects; Genetic polymorphisms; Genetics; Genotype & phenotype; Gynecology; Health aspects; Health risk assessment; Health risks; Humans; Inactivation; Kinases; MDM2 protein; Medical research; Medicine; Mutation; Obstetrics; p53 Protein; Patients; Polymorphism; Polymorphism, Genetic - genetics; Proportional Hazards Models; Real-Time Polymerase Chain Reaction; Risk; Risk Factors; Studies; Survival Analysis; Transcription factors; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047325

The TP53 Arg72Pro polymorphism encodes two p53 variants with different biochemical properties. Here we investigated the impact of this polymorphism on the expression of key p53 target genes in a panel of human breast carcinomas, breast cancer risk, and age at onset. The Arg72Pro polymorphism was genotyped in 270 breast cancer patients and 221 control subjects. In addition, the Arg72Pro genotype of 116 breast tumors was determined, and correlated with intratumoral mRNA expression of TP53 and its key target genes MDM2, p21, BAX, and PERP, as quantified by qRT-PCR. We found a significantly increased breast cancer risk associated with the Pro-allele (per-allele odds ratio, 1.46; 95% confidence interval, 1.08-1.99), and a significantly later mean age at breast cancer onset for Pro/Pro patients (63.2±18 years) compared to Arg/Arg patients (58.2±15 years). The frequency of somatic TP53 inactivation was 25.4% in Arg/Arg, 20.9% in Arg/Pro, and 16.7% in Pro/Pro patients, which may reflect a higher selective pressure to mutate the Arg-allele. The median mRNA levels of p21 and BAX in the tumors of Pro-allele carriers were significantly reduced to 55.7% and 76.9% compared to Arg/Arg patients, whereas p53, MDM2 and PERP expression were hardly altered. The p53(72Arg) variant appears to be a more potent in vivo transcription factor and tumor suppressor in human breast cancer than the p53(72Pro) variant. The Arg72Pro genotype has no significant effects in patients with TP53 mutated tumors, in which p53 is non-functional.