title: Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast 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 germline 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.
authors.affiliation: Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. s.vd.broek@nki.nl
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: van den Broek
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.forename: Sander V M
authors.initials: SV
authors.lastname: Canisius
authors.forename: Linde M
authors.initials: LM
authors.lastname: Braaf
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van't Veer
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human