appendIX 1 assoCIatIon of the GermlIne MDM2 snp309 and TP53 r72p varIants WIth breast CanCer survival in sPeciFic tumor subgrouPs

assoCIatIon of the GermlIne MDM2 snp309 and TP53 r72p varIants WIth breast CanCer survival in sPeciFic tumor subgrouPs. absTRacT The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair 'TP53 response pathway'. Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis < 53 years, n=295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germ-line MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a 'more aggressive phenotype' gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs TT-genotype HR 2.99, p=0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.