Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).
Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Hatef
H
Darabi
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Jonathan
J
Beesley
Département de Médecine Moléculaire, Faculté de Médecine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
Arnaud
A
Droit
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Siddhartha
S
Kar
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Silje
S
Nord
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Mahdi
M
Moradi Marjaneh
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
Penny
P
Soucy
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 Oncology, University of Cambridge, Cambridge, UK.
Maya
M
Ghoussaini
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Hanna
H
Fues Wahl
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 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.
Joe
J
Dennis
Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain.
M Rosario
MR
Alonso
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 Epidemiology, University of California Irvine, Irvine, CA, USA.
Hoda
H
Anton-Culver
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Volker
V
Arndt
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
Matthias W
MW
Beckmann
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
Javier
J
Benitez
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Natalia V
NV
Bogdanova
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Stig E
SE
Bojesen
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hiltrud
H
Brauch
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
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
Annegien
A
Broeks
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
Thomas
T
Brüning
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Barbara
B
Burwinkel
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 Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.
Ji-Yeob
JY
Choi
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Don M
DM
Conroy
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Fergus J
FJ
Couch
Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Angela
A
Cox
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
Simon S
SS
Cross
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Kamila
K
Czene
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Peter
P
Devilee
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Thilo
T
Dörk
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
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
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Olivia
O
Fletcher
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Henrik
H
Flyger
Vesalius Research Center, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
Eva
E
Galle
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Montserrat
M
García-Closas
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
Graham G
GG
Giles
Department of Medicine, McGill University, Montreal, Canada.|Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
Mark S
MS
Goldberg
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
Anna
A
González-Neira
Cancer &Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Pascal
P
Guénel
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Christopher A
CA
Haiman
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
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.|Department of Surgery, National University Health System, Singapore, Singapore.
Mikael
M
Hartman
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Antoinette
A
Hollestelle
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
John L
JL
Hopper
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
Hidemi
H
Ito
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Anna
A
Jakubowska
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Nichola
N
Johnson
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
Daehee
D
Kang
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Sofia
S
Khan
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
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Mieke
M
Kriege
Department of Cancer 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.
Vessela
V
Kristensen
Vesalius Research Center, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
Diether
D
Lambrechts
University of Hawaii Cancer Center, Honolulu, HI, USA.
Loic
L
Le Marchand
Department of Hematology-Oncology, National University Health System, Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Soo Chin
SC
Lee
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Annika
A
Lindblom
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
Artitaya
A
Lophatananon
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Jan
J
Lubinski
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
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.
Siranoush
S
Manoukian
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
Sara
S
Margolin
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
Keitaro
K
Matsuo
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Rebecca
R
Mayes
International Agency for Research on Cancer, Lyon, France.
James
J
McKay
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
Alfons
A
Meindl
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
Roger L
RL
Milne
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.|Institute of Population Health, University of Manchester, Manchester, UK.
Kenneth
K
Muir
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Susan L
SL
Neuhausen
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Heli
H
Nevanlinna
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Curtis
C
Olswold
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Nick
N
Orr
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
Paolo
P
Peterlongo
Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain.
Guillermo
G
Pita
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
Katri
K
Pylkäs
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Anja
A
Rudolph
National Cancer Institute, Bangkok, Thailand.
Suleeporn
S
Sangrajrang
Research Oncology, Guy's Hospital, King's College London, London, UK.
Elinor J
EJ
Sawyer
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
Marjanka K
MK
Schmidt
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.
Rita K
RK
Schmutzler
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Caroline
C
Seynaeve
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Mitul
M
Shah
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chen-Yang
CY
Shen
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Xiao-Ou
XO
Shu
Department of Pathology, The University of Melbourne, Melbourne, Australia.
Melissa C
MC
Southey
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Daniel O
DO
Stram
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Harald
H
Surowy
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.|Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Anthony
A
Swerdlow
Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.|Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
Soo H
SH
Teo
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
Daniel C
DC
Tessier
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
Ian
I
Tomlinson
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
Diana
D
Torres
Cancer &Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Thérèse
T
Truong
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Celine M
CM
Vachon
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
Daniel
D
Vincent
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
Robert
R
Winqvist
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Anna H
AH
Wu
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Pei-Ei
PE
Wu
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
Cheng Har
CH
Yip
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Wei
W
Zheng
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 Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Per
P
Hall
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Stacey L
SL
Edwards
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
Jacques
J
Simard
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Juliet D
JD
French
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Georgia
G
Chenevix-Trench
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Alison M
AM
Dunning
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*; D044465:White People
C498469:STXBP4 protein, human; D033921:Vesicular Transport Proteins