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

Painter JN, O'Mara TA, Batra J, Cheng T, Lose FA, Dennis J, Michailidou K, Tyrer JP, Ahmed S, Ferguson K, Healey CS, Kaufmann S, Hillman KM, Walpole C, Moya L, Pollock P, Jones A, Howarth K, Martin L, Gorman M, Hodgson S, Magdalena Echeverry De Polanco M, Sans M, Carracedo A, Castellvi-Bel S, Rojas-Martinez A, Santos E, Teixeira MR, Carvajal-Carmona L, Shu XO, Long J, Zheng W, Xiang YB, Montgomery GW, Webb PM, Scott RJ, Mcevoy M, Attia J, Holliday E, Martin NG, Nyholt DR, Henders AK, Fasching PA, Hein A, Beckmann M, Renner S, Doerk T, Hillemanns P, Duerst M, Runnebaum I, Lambrechts D, Coenegrachts L, Schrauwen S, Amant F, Winterhoff B, Dowdy SC, Goode EL, Teoman A, Salvesen HB, Trovik J, Njolstad TS, Werner HMJ, Ashton K, Proietto T, Otton G, Tzortzatos G, Mints M, Tham E, Hall P, Czene K, Liu J, Li J, Hopper JL, Southey MC, Ekici AB, Rübner M, Johnson N, Peto J, Burwinkel B, Marme F, Brenner H, Dieffenbach AK, Meindl A, Brauch H, Lindblom A, Depreeuw J, Moisse M, Chang-Claude J, Rudolph A, Couch FJ, Olson JE, Giles GG, Bruinsma F, Cunningham JM, Fridley BL, Borresen-Dale AL, Kristensen VN, Cox A, Swerdlow AJ, Orr N, Bolla MK, Wang Q, Weber RP, Chen Z, Shah M, French JD, Pharoah PDP, Dunning AM, Tomlinson I, Easton DF, Edwards SL, Thompson DJ, Spurdle AB (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 24

Pages Range: 1478-92

Journal Issue: 5

DOI: 10.1093/hmg/ddu552

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.

Authors with CRIS profile

Involved external institutions

Karolinska Institute Sweden (SE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Technische Universität München (TUM) Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Mayo Clinic United States (USA) (US) The University of Melbourne Australia (AU) Cancer Council Victoria Australia (AU) University of Kansas (KU) United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) University of Sheffield United Kingdom (GB) The Institute of Cancer Research (ICR) United Kingdom (GB) Hospital Clínic de Barcelona Spain (ES) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB) University of the Republic / Universidad de la República (UdelaR) Uruguay (UY) Queensland University of Technology (QUT) Australia (AU) University of Oxford United Kingdom (GB) University of Cambridge United Kingdom (GB) Universidad del Tolima Colombia (CO) Universidade de Santiago Compostela (USC) Spain (ES) Universidad Autónoma de Nuevo León Mexico (MX) A.C.Camargo Cancer Center Brazil (BR) Instituto Português de Oncologia Francisco Gentil (IPO) / Portuguese Oncology Institute Portugal (PT) Vanderbilt University United States (USA) (US) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) John Hunter Hospital Australia (AU) University of Newcastle (UoN) Australia (AU) University of California Los Angeles (UCLA) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Friedrich-Schiller-Universität Jena Germany (DE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University of Bergen / Universitetet i Bergen Norway (NO) Genome Institute of Singapore Singapore (SG) London School of Hygiene and Tropical Medicine United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Duke University United States (USA) (US) University of South Florida (USF) United States (USA) (US)

How to cite

APA:

Painter, J.N., O'Mara, T.A., Batra, J., Cheng, T., Lose, F.A., Dennis, J.,... Spurdle, A.B. (2015). Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Human Molecular Genetics, 24(5), 1478-92. https://dx.doi.org/10.1093/hmg/ddu552

MLA:

Painter, Jodie N., et al. "Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk." Human Molecular Genetics 24.5 (2015): 1478-92.

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