TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

kConFab/AOCS Investigators, Rainer Fagerholm, Sofia Khan, Marjanka K Schmidt, Montserrat García-Closas, Päivi Heikkilä, Jani Saarela, Jonathan Beesley, Maral Jamshidi, Kristiina Aittomäki, Jianjun Liu, H Raza Ali, Irene L Andrulis, Matthias W Beckmann, Sabine Behrens, Fiona M Blows, Hermann Brenner, Jenny Chang-Claude, Fergus J Couch, Kamila CzenePeter A Fasching, Jonine Figueroa, Giuseppe Floris, Gord Glendon, Qi Guo, Per Hall, Emily Hallberg, Ute Hamann, Bernd Holleczek, Maartje J Hooning, John L Hopper, Agnes Jager, Maria Kabisch, Renske Keeman, Veli-Matti Kosma, Diether Lambrechts, Annika Lindblom, Arto Mannermaa, Sara Margolin, Elena Provenzano, Mitul Shah, Melissa C Southey, Joe Dennis, Michael Lush, Kyriaki Michailidou, Qin Wang, Manjeet K Bolla, Alison M Dunning, Douglas F Easton, Paul D P Pharoah, Georgia Chenevix-Trench

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)18381-18398
Number of pages18
JournalOncotarget
Volume8
Issue number11
DOIs
Publication statusPublished - 5 Feb 2017

Keywords

  • Journal Article

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