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

J N Painter; T A O'Mara; J Batra; T Cheng; Felicity Lose; J Dennis; K Michailidou; J P Tyrer; S Ahmed; K Ferguson; C S Healey; S Kaufmann; K M Hillman; C Walpole; L Moya; P Pollock; A Jones; K Howarth; Lynn Martin; M Gorman; S Hodgson; M M E De Polanco; M Sans; A Carracedo; S Castellvi-Bel; A Rojas-Martinez; E Santos; M R Teixeira; L Carvajal-Carmona; X O Shu; J Long; W Zheng; Y B Xiang; G W Montgomery; P M Webb; R J Scott; M McEvoy; J Attia; E Holliday; N G Martin; D R Nyholt; A K Henders; P A Fasching; A Hein; M W Beckmann; S P Renner; T Dörk; P Hillemanns; M Dürst; I Runnebaum; D Lambrechts; L Coenegrachts; S Schrauwen; F Amant; B Winterhoff; S C Dowdy; E L Goode; A Teoman; H B Salvesen; J Trovik; T S Njolstad; H M J Werner; K Ashton; T Proietto; G Otton; G Tzortzatos; M Mints; E Tham; P Hall; K Czene; J Liu; Jingmei Li; J L Hopper; M C Southey; A B Ekici; M Ruebner; N Johnson; J Peto; B Burwinkel; F Marme; H Brenner; A K Dieffenbach; A Meindl; H Brauch; A Lindblom; J Depreeuw; M Moisse; J Chang-Claude; A Rudolph; F J Couch; J E Olson; G G Giles; F Bruinsma; J M Cunningham; B L Fridley; A L Børresen-Dale; V N Kristensen; A Cox; A J Swerdlow; N Orr; M K Bolla; Q Wang; R P Weber; Z Chen; M Shah; J D French; P D P Pharoah; A M Dunning; I Tomlinson; D F Easton; S L Edwards; D J Thompson; A B Spurdle

doi:10.1093/hmg/ddu552

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

Journal article

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

J N Painter, T A O'Mara, J Batra, T Cheng, Felicity Lose, J Dennis, K Michailidou, J P Tyrer, S Ahmed, K Ferguson, …

Human Molecular Genetics, Vol.24(5), pp.1478-1492

2015

DOI: https://doi.org/10.1093/hmg/ddu552

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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. © The Author 2014.

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Title: Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
Authors: J N Painter (Author)
T A O'Mara (Author)
J Batra (Author)
T Cheng (Author)
Felicity Lose (Author)
J Dennis (Author)
K Michailidou (Author)
J P Tyrer (Author)
S Ahmed (Author)
K Ferguson (Author)
C S Healey (Author)
S Kaufmann (Author)
K M Hillman (Author)
C Walpole (Author)
L Moya (Author)
P Pollock (Author)
A Jones (Author)
K Howarth (Author)
Lynn Martin (Author)
M Gorman (Author)
S Hodgson (Author)
M M E De Polanco (Author)
M Sans (Author)
A Carracedo (Author)
S Castellvi-Bel (Author)
A Rojas-Martinez (Author)
E Santos (Author)
M R Teixeira (Author)
L Carvajal-Carmona (Author)
X O Shu (Author)
J Long (Author)
W Zheng (Author)
Y B Xiang (Author)
G W Montgomery (Author)
P M Webb (Author)
R J Scott (Author)
M McEvoy (Author)
J Attia (Author)
E Holliday (Author)
N G Martin (Author)
D R Nyholt (Author)
A K Henders (Author)
P A Fasching (Author)
A Hein (Author)
M W Beckmann (Author)
S P Renner (Author)
T Dörk (Author)
P Hillemanns (Author)
M Dürst (Author)
I Runnebaum (Author)
D Lambrechts (Author)
L Coenegrachts (Author)
S Schrauwen (Author)
F Amant (Author)
B Winterhoff (Author)
S C Dowdy (Author)
E L Goode (Author)
A Teoman (Author)
H B Salvesen (Author)
J Trovik (Author)
T S Njolstad (Author)
H M J Werner (Author)
K Ashton (Author)
T Proietto (Author)
G Otton (Author)
G Tzortzatos (Author)
M Mints (Author)
E Tham (Author)
P Hall (Author)
K Czene (Author)
J Liu (Author)
Jingmei Li (Author)
J L Hopper (Author)
M C Southey (Author)
A B Ekici (Author)
M Ruebner (Author)
N Johnson (Author)
J Peto (Author)
B Burwinkel (Author)
F Marme (Author)
H Brenner (Author)
A K Dieffenbach (Author)
A Meindl (Author)
H Brauch (Author)
A Lindblom (Author)
J Depreeuw (Author)
M Moisse (Author)
J Chang-Claude (Author)
A Rudolph (Author)
F J Couch (Author)
J E Olson (Author)
G G Giles (Author)
F Bruinsma (Author)
J M Cunningham (Author)
B L Fridley (Author)
A L Børresen-Dale (Author)
V N Kristensen (Author)
A Cox (Author)
A J Swerdlow (Author)
N Orr (Author)
M K Bolla (Author)
Q Wang (Author)
R P Weber (Author)
Z Chen (Author)
M Shah (Author)
J D French (Author)
P D P Pharoah (Author)
A M Dunning (Author)
I Tomlinson (Author)
D F Easton (Author)
S L Edwards (Author)
D J Thompson (Author)
A B Spurdle (Author)
Publication details: Human Molecular Genetics, Vol.24(5), pp.1478-1492
Publisher: Oxford University Press
Date published: 2015
DOI: 10.1093/hmg/ddu552
ISSN: 0964-6906; 0964-6906
Copyright note: Copyright © 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.
Organisation Unit: Office of Research
Language: English
Record Identifier: 99450914702621
Output Type: Journal article

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