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Hum Genet. 2016 Jan;135(1):137-54. doi: 10.1007/s00439-015-1616-8. Epub 2015 Nov 30.

Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

Author information

1
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
2
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
3
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
4
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
5
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
6
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
7
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
8
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
9
Department of Pathology, The University of Melbourne, Melbourne, Australia.
10
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
11
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
12
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
13
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
14
Research Oncology, Guy's Hospital, King's College London, London, UK.
15
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
16
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
17
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
18
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
19
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
20
University Paris-Sud, Villejuif, France.
21
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
22
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
23
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
24
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
25
Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
26
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
27
Beckman Research Institute of City of Hope, Duarte, CA, USA.
28
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
30
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
31
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
32
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
33
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
34
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
35
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, Stuttgart, Germany.
36
University of Tübingen, Tübingen, Germany.
37
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
38
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
39
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
40
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
41
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
42
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
43
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
44
VIB Vesalius Research Center, Department of Oncology, University of Leuven, Leuven, Belgium.
45
Multidisciplinary Breast Center, University Hospitals Leuven, University of Leuven, Leuven, Belgium.
46
Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
47
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
48
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
49
IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
50
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
51
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
52
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
53
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
54
Department of Medicine, McGill University, Montreal, Canada.
55
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
56
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
57
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
58
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
59
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
60
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
61
Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland.
62
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
63
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
64
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
65
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
66
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
67
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
68
Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, UK.
69
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
70
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
71
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
72
Roswell Park Cancer Institute, Buffalo, NY, USA.
73
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
74
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
75
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. j.chang-claude@dkfz-heidelberg.de.
76
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.chang-claude@dkfz-heidelberg.de.

Abstract

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

PMID:
26621531
PMCID:
PMC4698282
DOI:
10.1007/s00439-015-1616-8
[Indexed for MEDLINE]
Free PMC Article

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