TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.
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.
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Rainer
R
Fagerholm
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Sofia
S
Khan
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Marjanka K
MK
Schmidt
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Montserrat
M
García-Closas
Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Päivi
P
Heikkilä
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
Jani
J
Saarela
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Jonathan
J
Beesley
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Maral
M
Jamshidi
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Kristiina
K
Aittomäki
Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
Jianjun
J
Liu
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Pathology, University of Cambridge, Cambridge, UK.
H Raza
HR
Ali
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Irene L
IL
Andrulis
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
Matthias W
MW
Beckmann
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sabine
S
Behrens
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Fiona M
FM
Blows
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.
Hermann
H
Brenner
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jenny
J
Chang-Claude
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Fergus J
FJ
Couch
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Kamila
K
Czene
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.
Peter A
PA
Fasching
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.
Jonine
J
Figueroa
Leuven Multidisciplinary Breast Center, Department of Oncology, KULeuven, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Giuseppe
G
Floris
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
Gord
G
Glendon
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Qi
Q
Guo
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Per
P
Hall
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Emily
E
Hallberg
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ute
U
Hamann
Saarland Cancer Registry, Saarbrücken, Germany.
Bernd
B
Holleczek
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Maartje J
MJ
Hooning
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
John L
JL
Hopper
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Agnes
A
Jager
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Maria
M
Kabisch
Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Renske
R
Keeman
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.
Veli-Matti
VM
Kosma
Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
Diether
D
Lambrechts
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Annika
A
Lindblom
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.
Arto
A
Mannermaa
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Sara
S
Margolin
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.
Elena
E
Provenzano
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Mitul
M
Shah
Department of Pathology, The University of Melbourne, Melbourne, Australia.
Melissa C
MC
Southey
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Joe
J
Dennis
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Michael
M
Lush
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.
Kyriaki
K
Michailidou
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Qin
Q
Wang
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Manjeet K
MK
Bolla
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Alison M
AM
Dunning
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.
Douglas F
DF
Easton
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.
Paul D P
PD
Pharoah
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Georgia
G
Chenevix-Trench
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.|Department of Oncology, University of Örebro, Örebro, Sweden.
Carl
C
Blomqvist
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Heli
H
Nevanlinna
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
D018943:Anthracyclines; D051017:Apoptosis Regulatory Proteins; C495901:TP53 protein, human; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; C584002:FBXO28 protein, human; D044843:SKP Cullin F-Box Protein Ligases
SNP; TP53; anthracycline; breast cancer; survival