title: 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.
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.
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Jieping
authors.initials: J
authors.lastname: Lei
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Behrens
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Bolla
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.affiliation: 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.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Haeberle
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Dos-Santos-Silva
authors.affiliation: Research Oncology, Guy's Hospital, King's College London, London, UK.
authors.forename: Elinor J
authors.initials: EJ
authors.lastname: Sawyer
authors.affiliation: Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Marmé
authors.affiliation: Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.|University Paris-Sud, Villejuif, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Guénel
authors.affiliation: Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.|University Paris-Sud, Villejuif, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Truong
authors.affiliation: Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.|Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.affiliation: Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Flyger
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Sune F
authors.initials: SF
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.affiliation: Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
authors.forename: Primitiva
authors.initials: P
authors.lastname: Menéndez
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.affiliation: Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arndt
authors.affiliation: Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.affiliation: Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.|Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.affiliation: Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogdanova
authors.affiliation: Cancer Center, Kuopio University Hospital, 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.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Cancer Center, Kuopio University Hospital, 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.
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.affiliation: VIB Vesalius Research Center, Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Laurien
authors.initials: L
authors.lastname: Van Dijck
authors.affiliation: Multidisciplinary Breast Center, University Hospitals Leuven, University of Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Smeets
authors.affiliation: Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Flesch-Janys
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Eilber
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Hallberg
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Fredrick
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.affiliation: Department of Medicine, McGill University, Montreal, Canada.|Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Goldberg
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Beeghly-Fadiel
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.|Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.affiliation: Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Grip
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
authors.forename: Gord
authors.initials: G
authors.lastname: Glendon
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Brand
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hatef
authors.initials: H
authors.lastname: Darabi
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.affiliation: Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kabisch
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
authors.forename: Diana
authors.initials: D
authors.lastname: Torres
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Foluso
authors.initials: F
authors.lastname: Ademuyiwa
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Swerdlow
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. j.chang-claude@dkfz-heidelberg.de.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.chang-claude@dkfz-heidelberg.de.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide