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

The GENICA Network

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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.

Original languageEnglish (US)
Pages (from-to)1478-1492
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2015

Fingerprint

Hepatocyte Nuclear Factor 1
Homeobox Genes
Endometrial Neoplasms
Single Nucleotide Polymorphism
Neoplasms
Gene Expression
Atlases
Linkage Disequilibrium
Genetic Promoter Regions
Epigenomics
Computer Simulation
Introns
Type 2 Diabetes Mellitus
Haplotypes
Alleles
Odds Ratio

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. / The GENICA Network.

In: Human Molecular Genetics, Vol. 24, No. 5, 01.03.2015, p. 1478-1492.

Research output: Contribution to journalArticle

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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.",
author = "{The GENICA Network} and Painter, {Jodie N.} and O'Mara, {Tracy A.} and Jyotsna Batra and Timothy Cheng and Lose, {Felicity A.} and Joe Dennis and Kyriaki Michailidou and Tyrer, {Jonathan P.} and Shahana Ahmed and Kaltin Ferguson and Healey, {Catherine S.} and Susanne Kaufmann and Hillman, {Kristine M.} and Carina Walpole and Leire Moya and Pamela Pollock and Angela Jones and Kimberley Howarth and Lynn Martin and Maggie Gorman and Shirley Hodgson and {De Polanco}, {Ma Magdalena Echeverry} and Monica Sans and Angel Carracedo and Sergi Castellvi-Bel and Augusto Rojas-Martinez and Erika Santos and Teixeira, {Manuel R.} and Luis Carvajal-Carmona and Shu, {Xiao Ou} and Jirong Long and Wei Zheng and Xiang, {Yong Bing} and Montgomery, {Grant W.} and Webb, {Penelope M.} and Scott, {Rodney J.} and Mark McEvoy and John Attia and Elizabeth Holliday and Martin, {Nicholas G.} and Nyholt, {Dale R.} and Henders, {Anjali K.} and Fasching, {Peter A.} and Alexander Hein and Beckmann, {Matthias W.} and Renner, {Stefan P.} and Thilo D{\"o}rk and Peter Hillemanns and Matthias D{\"u}rst and Ingo Runnebaum",
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AU - Castellvi-Bel, Sergi

AU - Rojas-Martinez, Augusto

AU - Santos, Erika

AU - Teixeira, Manuel R.

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AU - Xiang, Yong Bing

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AU - Scott, Rodney J.

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AB - 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.

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