Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/93444
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
Author: Painter, J.
O'Mara, T.
Batra, J.
Cheng, T.
Lose, F.
Dennis, J.
Michailidou, K.
Tyrer, J.
Ahmed, S.
Ferguson, K.
Healey, C.
Kaufmann, S.
Hillman, K.
Walpole, C.
Moya, L.
Pollock, P.
Jones, A.
Howarth, K.
Martin, L.
Gorman, M.
et al.
Citation: Human Molecular Genetics, 2015; 24(5):1478-1492
Publisher: Oxford University Press (OUP)
Issue Date: 2015
ISSN: 0964-6906
1460-2083
Statement of
Responsibility: 
Jodie N. Painter ... National Study of Endometrial Cancer Genetics Group (NSECG), CHIBCHAConsortium ... The Australian National Endometrial Cancer Study Group (ANECS) ... RENDOCAS ... Australian Ovarian Cancer Study (AOCS) ... The GENICA Network ... et al.
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.
Keywords: National Study of Endometrial Cancer Genetics Group (NSECG)
CHIBCHA Consortium
Australian National Endometrial Cancer Study Group (ANECS)
RENDOCAS
Australian Ovarian Cancer Study (AOCS)
GENICA Network
Cell Line, Tumor
Humans
Endometrial Neoplasms
RNA, Messenger
Risk Factors
Case-Control Studies
Chromosome Mapping
Computational Biology
Epigenesis, Genetic
Genotype
Haplotypes
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Alleles
Databases, Genetic
Female
Hepatocyte Nuclear Factor 1-beta
Promoter Regions, Genetic
Genetic Variation
Genome-Wide Association Study
Genetic Loci
White People
Description: Martin K. Oehler is a member of The Australian Ovarian Cancer Study Group
Rights: © 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.
DOI: 10.1093/hmg/ddu552
Grant ID: http://purl.org/au-research/grants/nhmrc/1031333
http://purl.org/au-research/grants/nhmrc/1058415
http://purl.org/au-research/grants/nhmrc/339435
http://purl.org/au-research/grants/nhmrc/552402
http://purl.org/au-research/grants/nhmrc/1031333
Published version: http://dx.doi.org/10.1093/hmg/ddu552
Appears in Collections:Aurora harvest 2
Medicine publications

Files in This Item:
File Description SizeFormat 
hdl_93444.pdfPublished version694.69 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.