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Hum Mol Genet. 2015 Mar 1;24(5):1478-92. doi: 10.1093/hmg/ddu552. Epub 2014 Nov 6.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Painter JN1, O'Mara TA1, Batra J2, Cheng T3, Lose FA1, Dennis J4, Michailidou K4, Tyrer JP5, Ahmed S5, Ferguson K1, Healey CS5, Kaufmann S1, Hillman KM1, Walpole C2, Moya L2, Pollock P6, Jones A3, Howarth K3, Martin L3, Gorman M3, Hodgson S7; National Study of Endometrial Cancer Genetics Group (NSECG); CHIBCHA Consortium, De Polanco MM8, Sans M9, Carracedo A10, Castellvi-Bel S11, Rojas-Martinez A12, Santos E13, Teixeira MR14, Carvajal-Carmona L15, Shu XO16, Long J16, Zheng W16, Xiang YB17; Australian National Endometrial Cancer Study Group (ANECS), Montgomery GW1, Webb PM1, Scott RJ18, McEvoy M19, Attia J20, Holliday E21, Martin NG1, Nyholt DR1, Henders AK1, Fasching PA22, Hein A23, Beckmann MW23, Renner SP23, Dörk T24, Hillemanns P25, Dürst M26, Runnebaum I26, Lambrechts D27, Coenegrachts L28, Schrauwen S28, Amant F28, Winterhoff B29, Dowdy SC29, Goode EL30, Teoman A29, Salvesen HB31, Trovik J31, Njolstad TS31, Werner HM31, Ashton K32, Proietto T33, Otton G33, Tzortzatos G34, Mints M34, Tham E35; RENDOCAS, Hall P36, Czene K36, Liu J37, Li J37, Hopper JL38, Southey MC39; Australian Ovarian Cancer Study (AOCS), Ekici AB40, Ruebner M23, Johnson N41, Peto J42, Burwinkel B43, Marme F44, Brenner H45, Dieffenbach AK45, Meindl A46, Brauch H47; GENICA Network, Lindblom A35, Depreeuw J48, Moisse M48, Chang-Claude J49, Rudolph A50, Couch FJ51, Olson JE30, Giles GG52, Bruinsma F53, Cunningham JM51, Fridley BL54, Børresen-Dale AL55, Kristensen VN56, Cox A57, Swerdlow AJ58, Orr N59, Bolla MK4, Wang Q4, Weber RP60, Chen Z61, Shah M5, French JD1, Pharoah PD5, Dunning AM5, Tomlinson I3, Easton DF62, Edwards SL1, Thompson DJ5, Spurdle AB63.

Collaborators (333)

Spurdle AB, Webb PM, Young J, McQuire L, Baron-Hay S, Bell D, Bonaventura A, Brand A, Braye S, Carter J, Chan F, Dalrymple C, Ferrier A, Gard G, Hacker N, Hogg R, Houghton R, Marsden D, McIlroy K, Otton G, Pather S, Proietto A, Robertson G, Scurry J, Sharma R, Wain G, Wong F, Armes J, Crandon A, Cummings M, Land R, Nicklin J, Perrin L, Obermair A, Ward B, Davy M, Dodd T, Miller J, Oehler M, Paramasivum S, Pierides J, Whitehead F, Blomfield P, Challis D, Neesham D, Pyman J, Quinn M, Rome R, Weitzer M, Brennan B, Hammond I, Leung Y, McCartney A, Stewart C, Thompson J, O'Brien S, Moore S, Ferguson K, Walsh M, Cicero R, Green L, Griffith J, Jackman L, Ranieri B, O'Brien M, Schultz P, Alexander B, Baxter C, Croy H, Fitzgerald A, Herron E, Hill C, Jones M, Maidens J, Marshall A, Martin K, Mayhew J, Minehan E, Roffe D, Shirley H, Steane H, Stenlake A, Ward A, Webb S, White J, de Polanco M, Bohórquez ME, Prieto R, Criollo A, Ramírez C, Estrada AP, Suárez JJ, Martinez AR, Rogatto S, Jnr SA, Santos EM, Sans M, Colistro V, Hidalgo PC, Mut P, Carracedo A, Ponte CR, Garcia IQ, Castellvi-Bel S, Teixeira M, de Almeida AB, Hamann U, Gilbert M, Tomlinson I, Adams M, Al-Samarraie A, Anwar S, Athavale R, Awad S, Bali A, Barnes A, Cawdell G, Chan S, Chin K, Cornes P, Crawford M, Cullimore J, Ghaem-Maghami S, Gornall R, Green J, Hall M, Harvey M, Hawe J, Head A, Herod J, Hingorani M, Hocking M, Holland C, Hollingsworth T, Hollingworth J, Ind T, Irvine R, Irwin C, Katesmark M, Kehoe S, Kheng-Chew G, Lankester K, Linder A, Luesley D, B-Lynch C, McFarlane V, Naik R, Nicholas N, Nugent D, Oates S, Oladipo A, Papadopoulos A, Pearson S, Radstone D, Raju S, Rathmell A, Redman C, Rymer M, Sarhanis P, Sparrow G, Stuart N, Sundar S, Thompson A, Tinkler S, Trent S, Tristram A, Walji N, Woolas R, Lindblom A, Tzortzatos G, Mints M, Tham E, Castro O, Gemzell-Danielsson K, Baker H, Baynes C, Conroy D, Curzon B, Harrington P, Irvine S, Luccarini C, Mayes R, Munday H, Perkins B, Pharoah D, Platte R, Stafford A, West J, Shu XO, Zheng W, Long J, Cai Q, Dai Q, Cai H, Delahanty R, Li C, Xiang YB, Gao Y, Xu WH, Lu W, Zheng Y, Gu K, Stuart-Harris R, Kirsten F, Rutovitz J, Clingan P, Glasgow A, Proietto A, Braye S, Otton G, Shannon J, Bonaventura T, Stewart J, Begbie S, Friedlander M, Bell D, Baron-Hay S, Ferrier A, Gard G, Nevell D, Pavlakis N, Valmadre S, Young B, Camaris C, Crouch R, Edwards L, Hacker N, Marsden D, Robertson G, Beale P, Beith J, Carter J, Dalrymple C, Houghton R, Russell P, Anderson L, Links M, Grygiel J, Hill J, Brand A, Byth K, Jaworski R, Harnett P, Sharma R, Wain G, Purdie D, Whiteman D, Ward B, Papadimos D, Crandon A, Cummings M, Horwood K, Obermair A, Perrin L, Wyld D, Nicklin J, Davy M, Oehler MK, Hall C, Dodd T, Healy T, Pittman K, Henderson D, Miller J, Pierdes J, Achan A, Blomfield P, Challis D, McIntosh R, Parker A, Brown B, Rome R, Allen D, Grant P, Hyde S, Robbie RL, Healy D, Jobling T, Manolitsas T, McNealage J, Rogers P, Susil B, Sumithran E, Simpson I, Haviv I, Phillips K, Rischin D, Fox S, Johnson D, Lade S, Waring P, Loughrey M, O'Callaghan N, Murray B, Mileshkin L, Allan P, Billson V, Pyman J, Neesham D, Quinn M, Hamilton A, Underhill C, Bell R, Ng LF, Blum R, Ganju V, Hammond I, McCartney A, Stewart C, Leung Y, Buck M, Zeps N, Bowtell DD, Green AC, Chenevix-Trench G, deFazio A, Gertig D, Webb PM, Bugert P, Arndt V, Müller H, Stegmaier C, Lo WY, Justenhoven C, Hamann U, Brüning T, Pesch B, Ko YD, Rabstein S, Lotz A, Baisch C, Fischer HP, Harth V.

Author information

1
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
2
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation, and School of Biomedical Science and.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and.
5
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
6
Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia.
7
Department of Clinical Genetics, St George's Hospital Medical School, London, UK.
8
Grupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia.
9
Department of Biological Anthropology, College of Humanities and Educational Sciences, University of the Republic, Magallanes, Montevideo, Uruguay.
10
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.
11
Genetic Predisposition to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Barcelona, Spain.
12
Universidad Autónoma de Nuevo León, Pedro de Alba s/n, San Nicolás de Los Garza, Nuevo León, Mexico.
13
Hospital A.C. Camargo, São Paulo, Brazil.
14
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal, Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
15
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.
16
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
17
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
18
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.
19
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
20
Hunter Medical Research Institute and, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health.
21
Hunter Medical Research Institute and, Centre for Information Based Medicine and School of Medicine and Public Health.
22
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.
23
University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
24
Gynaecology Research Unit and.
25
Clinics of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany.
26
Dept. of Gynaecology, Friedrich Schiller University Jena, Jena, Germany.
27
Vesalius Research Center, VIB, Leuven, Belgium, Department of Oncology, Laboratory for Translational Genetics.
28
Division of Gynaecological Oncology, Department of Oncology, University Hospital Leuven, KU Leuven, Belgium.
29
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology.
30
Division of Epidemiology, Department of Health Science Research and.
31
Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Norway, Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
32
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.
33
Faculty of Health, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
34
Department of Women's and Children's Health.
35
Department of Molecular Medicine and Surgery and.
36
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
37
Human Genetics, Genome Institute of Singapore, Singapore.
38
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and.
39
Department of Pathology, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, VIC, Australia.
40
Institute of Human Genetics, University Hospital, Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
41
Breakthrough Breast Cancer Research Centre.
42
London School of Hygiene and Tropical Medicine, London, UK.
43
Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Molecular Epidemiology, C080.
44
Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
45
Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
46
Division of Tumor Genetics, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.
47
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany.
48
Vesalius Research Center, VIB, Leuven, Belgium.
49
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
50
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
51
Departments of Laboratory Medicine and Pathology, and Health Science Research, Mayo Clinic, Rochester, MN, USA.
52
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.
53
Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia.
54
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
55
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.
56
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.
57
Department of Oncology, Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.
58
Division of Genetics and Epidemiology and, Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
59
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
60
Department of Community and Family Medicine, Duke University School of Medicine, Durham, NC, USA.
61
Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
62
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.
63
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, amanda.spurdle@qimrberghofer.edu.au.

Abstract

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.

PMID:
25378557
PMCID:
PMC4321445
DOI:
10.1093/hmg/ddu552
[Indexed for MEDLINE]
Free PMC Article

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