Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Jodie N
JN
Painter
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Tracy A
TA
O'Mara
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Jyotsna
J
Batra
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Timothy
T
Cheng
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Felicity A
FA
Lose
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Joe
J
Dennis
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Kyriaki
K
Michailidou
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Jonathan P
JP
Tyrer
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Shahana
S
Ahmed
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Kaltin
K
Ferguson
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Catherine S
CS
Healey
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Susanne
S
Kaufmann
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Kristine M
KM
Hillman
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Carina
C
Walpole
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
Leire
L
Moya
Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia.
Pamela
P
Pollock
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Angela
A
Jones
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Kimberley
K
Howarth
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lynn
L
Martin
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Maggie
M
Gorman
Department of Clinical Genetics, St George's Hospital Medical School, London, UK.
Shirley
S
Hodgson
Grupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia.
Ma Magdalena Echeverry
MM
De Polanco
Department of Biological Anthropology, College of Humanities and Educational Sciences, University of the Republic, Magallanes, Montevideo, Uruguay.
Monica
M
Sans
Grupo de Medicina Xenómica, Fundación Galega de Medicina Xenómica (SERGAS) and CIBERER, Universidade de Santiago de Compostela, Santiago de Compostela, Spain, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, KSA.
Angel
A
Carracedo
Genetic Predisposition to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Barcelona, Spain.
Sergi
S
Castellvi-Bel
Universidad Autónoma de Nuevo León, Pedro de Alba s/n, San Nicolás de Los Garza, Nuevo León, Mexico.
Augusto
A
Rojas-Martinez
Hospital A.C. Camargo, São Paulo, Brazil.
Erika
E
Santos
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal, Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
Manuel R
MR
Teixeira
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Grupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia, Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
Luis
L
Carvajal-Carmona
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiao-Ou
XO
Shu
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Jirong
J
Long
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Wei
W
Zheng
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
Yong-Bing
YB
Xiang
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Grant W
GW
Montgomery
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Penelope M
PM
Webb
Hunter Medical Research Institute and, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia, Centre for Information Based Medicine and School of Biomedical Science and Pharmacy.
Rodney J
RJ
Scott
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
Mark
M
McEvoy
Hunter Medical Research Institute and, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
John
J
Attia
Hunter Medical Research Institute and, Centre for Information Based Medicine and School of Medicine and Public Health.
Elizabeth
E
Holliday
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Nicholas G
NG
Martin
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Dale R
DR
Nyholt
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Anjali K
AK
Henders
Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Peter A
PA
Fasching
University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Alexander
A
Hein
University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Matthias W
MW
Beckmann
University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Stefan P
SP
Renner
Gynaecology Research Unit and.
Thilo
T
Dörk
Clinics of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany.
Peter
P
Hillemanns
Dept. of Gynaecology, Friedrich Schiller University Jena, Jena, Germany.
Matthias
M
Dürst
Dept. of Gynaecology, Friedrich Schiller University Jena, Jena, Germany.
Ingo
I
Runnebaum
Vesalius Research Center, VIB, Leuven, Belgium, Department of Oncology, Laboratory for Translational Genetics.
Diether
D
Lambrechts
Division of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Lieve
L
Coenegrachts
Division of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Stefanie
S
Schrauwen
Division of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
Frederic
F
Amant
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Boris
B
Winterhoff
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Sean C
SC
Dowdy
Division of Epidemiology, Department of Health Science Research and.
Ellen L
EL
Goode
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology.
Attila
A
Teoman
Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Helga B
HB
Salvesen
Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Jone
J
Trovik
Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Tormund S
TS
Njolstad
Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
Henrica M J
HM
Werner
Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia, Faculty of Health, Centre for Information Based Medicine and the Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy and.
Katie
K
Ashton
Faculty of Health, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
Tony
T
Proietto
Faculty of Health, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
Geoffrey
G
Otton
Department of Women's and Children's Health.
Gerasimos
G
Tzortzatos
Department of Women's and Children's Health.
Miriam
M
Mints
Department of Molecular Medicine and Surgery and.
Emma
E
Tham
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Per
P
Hall
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Kamila
K
Czene
Human Genetics, Genome Institute of Singapore, Singapore.
Jianjun
J
Liu
Human Genetics, Genome Institute of Singapore, Singapore.
Jingmei
J
Li
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and.
John L
JL
Hopper
Department of Pathology, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, VIC, Australia.
Melissa C
MC
Southey
Institute of Human Genetics, University Hospital, Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Arif B
AB
Ekici
University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Matthias
M
Ruebner
Breakthrough Breast Cancer Research Centre.
Nicola
N
Johnson
London School of Hygiene and Tropical Medicine, London, UK.
Julian
J
Peto
Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Molecular Epidemiology, C080.
Barbara
B
Burwinkel
Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
Frederik
F
Marme
Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
Hermann
H
Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
Aida K
AK
Dieffenbach
Division of Tumor Genetics, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.
Alfons
A
Meindl
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany.
Hiltrud
H
Brauch
Department of Molecular Medicine and Surgery and.
Annika
A
Lindblom
Vesalius Research Center, VIB, Leuven, Belgium.
Jeroen
J
Depreeuw
Vesalius Research Center, VIB, Leuven, Belgium.
Matthieu
M
Moisse
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jenny
J
Chang-Claude
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
Anja
A
Rudolph
Departments of Laboratory Medicine and Pathology, and Health Science Research, Mayo Clinic, Rochester, MN, USA.
Fergus J
FJ
Couch
Division of Epidemiology, Department of Health Science Research and.
Janet E
JE
Olson
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
Graham G
GG
Giles
Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia.
Fiona
F
Bruinsma
Departments of Laboratory Medicine and Pathology, and Health Science Research, Mayo Clinic, Rochester, MN, USA.
Julie M
JM
Cunningham
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
Brooke L
BL
Fridley
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway, Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
Anne-Lise
AL
Børresen-Dale
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway, Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway, Division of Medicine, Department of Clinical Molecular Oncology, Akershus University Hospital, Ahus, Norway.
Vessela N
VN
Kristensen
Department of Oncology, Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.
Angela
A
Cox
Division of Genetics and Epidemiology and, Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
Anthony J
AJ
Swerdlow
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
Nicholas
N
Orr
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Manjeet K
MK
Bolla
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
Qin
Q
Wang
Department of Community and Family Medicine, Duke University School of Medicine, Durham, NC, USA.
Rachel Palmieri
RP
Weber
Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
Zhihua
Z
Chen
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Mitul
M
Shah
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Juliet D
JD
French
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Paul D P
PD
Pharoah
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Alison M
AM
Dunning
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Ian
I
Tomlinson
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Douglas F
DF
Easton
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Stacey L
SL
Edwards
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Deborah J
DJ
Thompson
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, amanda.spurdle@qimrberghofer.edu.au.
Amanda B
AB
Spurdle
D000483:Alleles; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D019295:Computational Biology; D030541:Databases, Genetic; D016889:Endometrial Neoplasms / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D044465:White People / Q000235:genetics
C496495:HNF1B protein, human; D012333:RNA, Messenger; D051539:Hepatocyte Nuclear Factor 1-beta