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

Jodie N Painter, Tracy A O'Mara, Jyotsna Batra, Timothy Cheng, Felicity A Lose, Joe Dennis, Kyriaki Michailidou, Jonathan Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine Healey, Susanne Kaufmann, Kristine M Hillman, Carina M Walpole, Leire Moya, Pamela Pollock, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie GormanShirley Hodgson, National Study of Endometrial Cancer Genetics Group (NSECG), CHIBCHA Consortium, Ma. Magdalena Echeverry De Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Erika Maria Monteiro Santos, Manuel R Teixeira, Luis Carvajal-Carmona, Xiao-Ou Shu, Jirong Long, Wei Zheng, Yong-Bing Xiang, The Australian National Endometrial Cancer Study Group (ANECS), Grant W Montgomery, Penelope M Webb, Rodney J Scott, Mark McEvoy, John R Attia, Elizabeth G Holliday, Nicholas G Martin, Dale R Nyholt, Alexander Hein, Matthias Beckmann, Stefan P Renner, Thilo Dork, Peter Hillemanns, Matthias Duerst, Ingo B Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic J Amant, Boris Winterhoff, Sean C Dowdy, Ellen L Goode, Attila Teoman, Helga Birgitte Salvesen, Jone Trovik, Tormund S Njolstad, Henrica Maria Johanna Werner, Katie Ashton, Anthony Proietto, Geoffrey Otton, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, RENDOCAS, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L Hopper, Melissa Caroline Southey, Australian Ovarian Cancer Study Group (AOCS), The GENICA Network

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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 genotypewas associatedwithHNF1BmRNAexpression butnotwithHNF1Bmethylationinendometrial tumor samples fromThe 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 chromatinmarks extending fromtheminimal 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 associatedwith endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression
Original languageEnglish
Pages (from-to)1478-1492
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number5
DOIs
Publication statusPublished - 2015

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