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 P. Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S. Healey, Susanne Kaufmann, Kristine M. Hillman, Carina Walpole, Leire Moya, Pamela Pollock, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie GormanShirley Hodgson, Ma Magdalena Echeverry De Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Erika Santos, Manuel R. Teixeira, Luis Carvajal-Carmona, Xiao Ou Shu, Jirong Long, Wei Zheng, Yong Bing Xiang, Grant W. Montgomery, Penelope M. Webb, Rodney J. Scott, Mark McEvoy, John Attia, Elizabeth Holliday, Nicholas G. Martin, Dale R. Nyholt, Anjali K. Henders, Peter A. Fasching, Alexander Hein, Matthias W. Beckmann, Stefan P. Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic Amant, Boris Winterhoff, Sean C. Dowdy, Ellen L. Goode, Attila Teoman, Helga B. Salvesen, Jone Trovik, Tormund S. Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L. Hopper, Melissa C. Southey, Arif B. Ekici, Matthias Ruebner, Nicola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K. Dieffenbach, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Fiona Bruinsma, Julie M. Cunningham, Brooke L. Fridley, Anne Lise Børresen-Dale, Vessela N. Kristensen, Angela Cox, Anthony J. Swerdlow, Nicholas Orr, Manjeet K. Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Juliet D. French, Paul D P Pharoah, Alison M. Dunning, Ian Tomlinson, Douglas F. Easton, Stacey L. Edwards, Deborah J. Thompson, Amanda B. Spurdle

Research output: Contribution to journalArticle

36 Scopus citations

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 (US)
Pages (from-to)1478-1492
Number of pages15
JournalHuman molecular genetics
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2015

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    Painter, J. N., O'Mara, T. A., Batra, J., Cheng, T., Lose, F. A., Dennis, J., Michailidou, K., Tyrer, J. P., Ahmed, S., Ferguson, K., Healey, C. S., Kaufmann, S., Hillman, K. M., Walpole, C., Moya, L., Pollock, P., Jones, A., Howarth, K., Martin, L., ... Spurdle, A. B. (2015). Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Human molecular genetics, 24(5), 1478-1492. https://doi.org/10.1093/hmg/ddu552