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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.
Helsinki University Hospital, Helsinki, Finland.
Helsinki University Hospital, Helsinki, Finland.
Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
National Cancer Institute, Rockville MD, United States.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 11, 18381-18398 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Impact press, 2017. Vol. 8, no 11, 18381-18398 p.
Keyword [en]
SNP, TP53, anthracycline, breast cancer, survival
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-57398DOI: 10.18632/oncotarget.15110ISI: 000396877500082PubMedID: 28179588Scopus ID: 2-s2.0-85015243706OAI: oai:DiVA.org:oru-57398DiVA: diva2:1092429
Note

Funding agencieas:

Cancer Research UK  C1287/A10118 C1287/A12014 C1287/A 10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 

European Community's Seventh Framework Programme  223175 HEALTH-F2-2009-223175 

National Institutes of Health  CA128978 

Post-Cancer GWAS initiative  1U19 CA148537 1U19 CA148065 1U19 CA148112 

Department of Defence  W81XWH-10-1-0341 

Canadian Institutes of Health Research (CIHR)   

Komen Foundation for the Cure   

Breast Cancer Research Foundation   

Ovarian Cancer Research Fund   

National Cancer Institute (USA) 

UM1 CA164920 National Health and Medical Research Council of Australia   

New South Wales Cancer Council   

Victorian Health Promotion Foundation (Australia)   

Victorian Breast Cancer Research Consortium   

Dutch Cancer Society  NKI 2007-3839 2009 4363 ELAN-Fond of the University Hospital of Erlangen   Baden Wurttemberg Ministry of Science, Research and Arts 

 German Cancer Aid (Deutsche Krebshilfe)   

Helsinki University Central Hospital Research Fund   

Academy of Finland  266528 Finnish Cancer Society   

Nordic Cancer Union   

Sigrid Juselius Foundation   

Stockholm County Council   

Karolinska Institutet   

Swedish Cancer Society   

Gustav V Jubilee foundation   

Bert von Kantzows foundation   

Kuopio University Hospital grants   

Cancer Fund of North Savo   

Finnish Cancer Organizations   

University of Eastern Finland   

National Breast Cancer Foundation   

United States Army Medical Research and Materiel Command  DAMD17-01-1-0729 

Cancer Council Victoria   

Queensland Cancer Fund   

Cancer Council New South Wales   

Cancer Council South Australia   

Cancer Foundation of Western Australia   

Cancer Council Tasmania   

National Health and Medical Research

Council of Australia (NHMRC)  400413 400281 199600 

Stichting tegen Kanker'  232-2008 196-2010 FWO   

Deutsche Krebshilfe e.V.  70-2892-BR I 106332 108253 108419 

Hamburg Cancer Society   

German Cancer Research Center (DKFZ)   

Federal Ministry of Education and Research (BMBF) Germany  01KH0402 NIH  CA192393 CA116167 CA176785 

NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer  CA116201 

Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA   

Agency for Science, Technology and Research of Singapore (A*STAR)   

US National Institute of Health (NIH)   

Susan G. Komen Breast Cancer Foundation   

UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge   

DKFZ  KULPFV/10/016-SymBioSysII  

Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2017-05-02Bibliographically approved

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