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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; et al. 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; National Study of Endometrial Cancer Genetics Group (NSECG); CHIBCHA Consortium; De Polanco, MM; 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; Australian National Endometrial Cancer Study Group (ANECS); Montgomery, GW; Webb, PM; Scott, RJ; McEvoy, M; Attia, J; Holliday, E; Martin, NG; Nyholt, DR; Henders, AK; Fasching, PA; Hein, A; Beckmann, MW; Renner, SP; Dörk, T; Hillemanns, P; Dürst, 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, HM; Ashton, K; Proietto, T; Otton, G; Tzortzatos, G; Mints, M; Tham, E; RENDOCAS; Hall, P; Czene, K; Liu, J; Li, J; Hopper, JL; Southey, MC; Australian Ovarian Cancer Study (AOCS); Ekici, AB; Ruebner, M; Johnson, N; Peto, J; Burwinkel, B; Marme, F; Brenner, H; Dieffenbach, AK; Meindl, A; Brauch, H; GENICA Network; Lindblom, A; Depreeuw, J; Moisse, M; Chang-Claude, J; Rudolph, A; Couch, FJ; Olson, JE; Giles, GG; Bruinsma, F; Cunningham, JM; Fridley, BL; Børresen-Dale, AL; Kristensen, VN; Cox, A; Swerdlow, AJ; Orr, N; Bolla, MK; Wang, Q; Weber, RP; Chen, Z; Shah, M; French, JD; Pharoah, PD; Dunning, AM; Tomlinson, I; Easton, DF; Edwards, SL; Thompson, DJ; Spurdle, AB (2015) Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Human Molecular Genetics, 24 (5). pp. 1478-1492. ISSN 1460-2083 https://doi.org/10.1093/hmg/ddu552
SGUL Authors: Hodgson, Shirley Victoria

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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 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.

Item Type: Article
Additional Information: © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Human Molecular Genetics
ISSN: 1460-2083
Language: eng
Dates:
DateEvent
1 March 2015Published
Projects:
Project IDFunderFunder ID
068545/Z/02Wellcome TrustUNSPECIFIED
085475Wellcome TrustUNSPECIFIED
090532Wellcome TrustUNSPECIFIED
1U19 CA148065NCI NIH HHSUNSPECIFIED
1U19 CA148112NCI NIH HHSUNSPECIFIED
1U19 CA148537NCI NIH HHSUNSPECIFIED
C12292/A11174Cancer Research UKUNSPECIFIED
C1281/A12014Cancer Research UKUNSPECIFIED
C1287/A 10710Cancer Research UKUNSPECIFIED
C1287/A10118Cancer Research UKUNSPECIFIED
C1287/A12014Cancer Research UKUNSPECIFIED
C490/A10124Cancer Research UKUNSPECIFIED
C5047/A10692Cancer Research UKUNSPECIFIED
C5047/A15007Cancer Research UKUNSPECIFIED
C5047/A8384Cancer Research UKUNSPECIFIED
CA128978NCI NIH HHSUNSPECIFIED
G0000934Medical Research CouncilUNSPECIFIED
P50 CA136393NCI NIH HHSUNSPECIFIED
R01 CA 092585NCI NIH HHSUNSPECIFIED
R01 CA122443NCI NIH HHSUNSPECIFIED
R01 CA64277NCI NIH HHSUNSPECIFIED
R01 CA90899NCI NIH HHSUNSPECIFIED
U19 CA148112NCI NIH HHSUNSPECIFIED
UNSPECIFIEDCanadian Institutes of Health ResearchUNSPECIFIED
PubMed ID: 25378557
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107373
Publisher's version: https://doi.org/10.1093/hmg/ddu552

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