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

Autor: Fagerholm R; Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Khan S; Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Schmidt MK; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., García-Closas M; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Heikkilä P; Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Saarela J; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland., Beesley J; Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Jamshidi M; Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Aittomäki K; Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Liu J; Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore., Ali HR; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.; Department of Pathology, University of Cambridge, Cambridge, UK., Andrulis IL; Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Canada., Beckmann MW; Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany., Behrens S; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Blows FM; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Brenner H; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany., Chang-Claude J; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Couch FJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Czene K; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Fasching PA; Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA., Figueroa J; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Floris G; Leuven Multidisciplinary Breast Center, Department of Oncology, KULeuven, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium., Glendon G; Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada., Guo Q; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Hall P; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Hallberg E; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA., Hamann U; Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Holleczek B; Saarland Cancer Registry, Saarbrücken, Germany., Hooning MJ; Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Hopper JL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia., Jager A; Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Kabisch M; Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Keeman R; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Kosma VM; Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.; Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland., Lambrechts D; Vesalius Research Center, VIB, Leuven, Belgium.; Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium., Lindblom A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Mannermaa A; Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.; Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland., Margolin S; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Provenzano E; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.; Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.; Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK., Shah M; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Southey MC; Department of Pathology, The University of Melbourne, Melbourne, Australia., Dennis J; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Lush M; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Michailidou K; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus., Wang Q; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Bolla MK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Dunning AM; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Easton DF; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Pharoah PD; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Chenevix-Trench G; Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Blomqvist C; Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.; Department of Oncology, University of Örebro, Örebro, Sweden., Nevanlinna H; Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2017 Mar 14; Vol. 8 (11), pp. 18381-18398.
DOI: 10.18632/oncotarget.15110
Abstrakt: 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.
Databáze: MEDLINE