Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.
BACKGROUND
A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.


METHODS
We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.


RESULTS
Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.


CONCLUSIONS
Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.


CONCLUSIONS
Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Xingyi
X
Guo
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Jirong
J
Long
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Chenjie
C
Zeng
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Kyriaki
K
Michailidou
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
Maya
M
Ghoussaini
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Manjeet K
MK
Bolla
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Qin
Q
Wang
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia.
Roger L
RL
Milne
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Xiao-Ou
XO
Shu
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Qiuyin
Q
Cai
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Jonathan
J
Beesley
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
Siddhartha P
SP
Kar
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, California.
Hoda
H
Anton-Culver
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
Volker
V
Arndt
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Matthias W
MW
Beckmann
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Alicia
A
Beeghly-Fadiel
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain. Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
Javier
J
Benitez
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. International Epidemiology Institute, Rockville, Maryland.
William
W
Blot
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Natalia
N
Bogdanova
Copenhagen General Population Study, Herlev 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.
Stig E
SE
Bojesen
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. University of Tübingen, Tübingen, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
Hiltrud
H
Brauch
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hermann
H
Brenner
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Louise
L
Brinton
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, Bochum, Germany.
Thomas
T
Brüning
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
Barbara
B
Burwinkel
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Hui
H
Cai
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Sander
S
Canisius
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Jenny
J
Chang-Claude
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Ji-Yeob
JY
Choi
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Fergus J
FJ
Couch
Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
Angela
A
Cox
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
Simon S
SS
Cross
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Kamila
K
Czene
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Hatef
H
Darabi
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Peter
P
Devilee
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec, Canada.
Arnaud
A
Droit
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Thilo
T
Dörk
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California.
Peter A
PA
Fasching
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
Olivia
O
Fletcher
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
Henrik
H
Flyger
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
Florentia
F
Fostira
International Agency for Research on Cancer, Lyon, France.
Valerie
V
Gaborieau
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
Montserrat
M
García-Closas
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia.
Graham G
GG
Giles
Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland.
Mervi
M
Grip
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France. University Paris-Sud, Villejuif, France.
Pascal
P
Guénel
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Christopher A
CA
Haiman
Molecular Genetics of Breast Cancer, German Cancer Research Center, 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.
Mikael
M
Hartman
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Antoinette
A
Hollestelle
Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia.
John L
JL
Hopper
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chia-Ni
CN
Hsiung
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan.
Hidemi
H
Ito
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Anna
A
Jakubowska
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
Nichola
N
Johnson
Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
Maria
M
Kabisch
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
Daehee
D
Kang
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Sofia
S
Khan
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Julia A
JA
Knight
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
Veli-Matti
VM
Kosma
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, Hawaii.
Loic
L
Le Marchand
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Jingmei
J
Li
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Annika
A
Lindblom
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, United Kingdom.
Artitaya
A
Lophatananon
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Jan
J
Lubinski
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
Arto
A
Mannermaa
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
Siranoush
S
Manoukian
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
Sara
S
Margolin
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
Frederik
F
Marme
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
Keitaro
K
Matsuo
Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia.
Catriona A
CA
McLean
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
Alfons
A
Meindl
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy. Institute of Population Health, University of Manchester, Manchester, United Kingdom.
Kenneth
K
Muir
Beckman Research Institute of City of Hope, Duarte, California.
Susan L
SL
Neuhausen
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Heli
H
Nevanlinna
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen, Oslo, Norway. K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien, Oslo, Norway.
Silje
S
Nord
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
Janet E
JE
Olson
Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom; Cancer Research, Institute of Cancer Research, London, United Kingdom.
Nick
N
Orr
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
Paolo
P
Peterlongo
Department of Pathology, National University Health System, Singapore.
Thomas Choudary
TC
Putti
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Anja
A
Rudolph
National Cancer Institute, Bangkok, Thailand.
Suleeporn
S
Sangrajrang
Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
Elinor J
EJ
Sawyer
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Marjanka K
MK
Schmidt
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany. Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
Rita K
RK
Schmutzler
School of Public Health, China Medical University, Taichung, Taiwan. Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chen-Yang
CY
Shen
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Jiajun
J
Shi
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Martha J
MJ
Shrubsole
Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
Melissa C
MC
Southey
Division of Genetics and Epidemiology and Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom.
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 Hwang
SH
Teo
Vesalius Research Center, Leuven, Belgium. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
Bernard
B
Thienpont
Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Amanda Ewart
AE
Toland
Department of Surgical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
Robert A E M
RA
Tollenaar
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Ian P M
IP
Tomlinson
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France. University Paris-Sud, Villejuif, France.
Thérèse
T
Truong
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Chiu-Chen
CC
Tseng
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Ans
A
van den Ouweland
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Wanqing
W
Wen
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
Robert
R
Winqvist
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Anna
A
Wu
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
Cheng Har
CH
Yip
Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
M Pilar
MP
Zamora
Shanghai Municipal Center for Disease Control and Prevention, Shanghai, PR China.
Ying
Y
Zheng
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Per
P
Hall
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
Paul D P
PD
Pharoah
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec, Canada.
Jacques
J
Simard
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, United Kingdom.
Alison M
AM
Dunning
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
Douglas F
DF
Easton
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. wei.zheng@vanderbilt.edu.
Wei
W
Zheng
D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
D005819:Genetic Markers