Title |
Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
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Published in |
Human Molecular Genetics, November 2014
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DOI | 10.1093/hmg/ddu552 |
Pubmed ID | |
Authors |
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 Gorman, Shirley Hodgson, Study of Endometrial Cancer Genetics Group, CHIBCHA Consortium, 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, The Australian National Endometrial Cancer Study Group, 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, RENDOCAS, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L. Hopper, Melissa C. Southey, Australian Ovarian Cancer Study, Arif B. Ekici, Matthias Ruebner, Nicola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K. Dieffenbach, Alfons Meindl, Hiltrud Brauch, The GENICA Network, 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 |
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 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=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 tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Brazil | 2 | 2% |
Uruguay | 2 | 2% |
Mexico | 1 | <1% |
Unknown | 116 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 25 | 21% |
Student > Master | 16 | 13% |
Student > Ph. D. Student | 15 | 12% |
Student > Bachelor | 9 | 7% |
Professor > Associate Professor | 8 | 7% |
Other | 26 | 21% |
Unknown | 22 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 36 | 30% |
Medicine and Dentistry | 20 | 17% |
Agricultural and Biological Sciences | 16 | 13% |
Social Sciences | 6 | 5% |
Engineering | 3 | 2% |
Other | 11 | 9% |
Unknown | 29 | 24% |