R Fagerholm, S Khan, MK Schmidt, M García-Closas, P Heikkilä, J Saarela, J Beesley, M Jamshidi, K Aittomäki, J Liu, HR Ali, IL Andrulis, MW Beckmann, S Behrens, FM Blows, H Brenner, J Chang-Claude, FJ Couch, K Czene, PA Fasching, J Figueroa, G Floris, G Glendon, Q Guo, P Hall, E Hallberg, U Hamann, B Holleczek, MJ Hooning, JL Hopper, A Jager, M Kabisch, kConFab/AOCS Investigators, R Keeman, V-M Kosma, D Lambrechts, A Lindblom, A Mannermaa, S Margolin, E Provenzano, M Shah, MC Southey, J Dennis, M Lush, K Michailidou, Q Wang, MK Bolla, AM Dunning, DF Easton, PDP Pharoah, G Chenevix-Trench, C Blomqvist, H Nevanlinna
TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.