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, F.A. 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, L. Martin, M. Gorman & 63 others 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, J. Li, J.L. Hopper, M.C. Southey, A.B. Ekici, M. Ruebner, N. Johnson, Yee Leung, J. Peto, B. Burwinkel, F. Marme, H. Brenner, A.K. Dieffenbach

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    © The Author 2014. 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
    Pages (from-to)1478-1492
    JournalHuman Molecular Genetics
    Volume24
    Issue number5
    DOIs
    Publication statusPublished - 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

    Cite this

    Painter, J. N., O'Mara, T. A., Batra, J., Cheng, T., Lose, F. A., Dennis, J., ... Dieffenbach, A. K. (2015). Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Human Molecular Genetics, 24(5), 1478-1492. https://doi.org/10.1093/hmg/ddu552
    Painter, J.N. ; O'Mara, T.A. ; Batra, J. ; Cheng, T. ; Lose, F.A. ; Dennis, J. ; Michailidou, K. ; Tyrer, J.P. ; Ahmed, S. ; Ferguson, K. ; Healey, C.S. ; Kaufmann, S. ; Hillman, K.M. ; Walpole, C. ; Moya, L. ; Pollock, P. ; Jones, A. ; Howarth, K. ; Martin, L. ; Gorman, M. ; Hodgson, S. ; De Polanco, M.M.E. ; Sans, M. ; Carracedo, A. ; Castellvi-Bel, S. ; Rojas-Martinez, A. ; Santos, E. ; Teixeira, M.R. ; Carvajal-Carmona, L. ; Shu, X.O. ; Long, J. ; Zheng, W. ; Xiang, Y.B. ; Montgomery, G.W. ; Webb, P.M. ; Scott, R.J. ; Mcevoy, M. ; Attia, J. ; Holliday, E. ; Martin, N.G. ; Nyholt, D.R. ; Henders, A.K. ; Fasching, P.A. ; Hein, A. ; Beckmann, M.W. ; Renner, S.P. ; Dörk, T. ; Hillemanns, P. ; Dürst, M. ; Runnebaum, I. ; Lambrechts, D. ; Coenegrachts, L. ; Schrauwen, S. ; Amant, F. ; Winterhoff, B. ; Dowdy, S.C. ; Goode, E.L. ; Teoman, A. ; Salvesen, H.B. ; Trovik, J. ; Njolstad, T.S. ; Werner, H.M.J. ; Ashton, K. ; Proietto, T. ; Otton, G. ; Tzortzatos, G. ; Mints, M. ; Tham, E. ; Hall, P. ; Czene, K. ; Liu, J. ; Li, J. ; Hopper, J.L. ; Southey, M.C. ; Ekici, A.B. ; Ruebner, M. ; Johnson, N. ; Leung, Yee ; Peto, J. ; Burwinkel, B. ; Marme, F. ; Brenner, H. ; Dieffenbach, A.K. / Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 5. pp. 1478-1492.
    @article{176940ac90464335a4369ceeb64f5ddc,
    title = "Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk",
    abstract = "{\circledC} The Author 2014. 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 = "J.N. Painter and T.A. O'Mara and J. Batra and T. Cheng and F.A. Lose and J. Dennis and K. Michailidou and J.P. Tyrer and S. Ahmed and K. Ferguson and C.S. Healey and S. Kaufmann and K.M. Hillman and C. Walpole and L. Moya and P. Pollock and A. Jones and K. Howarth and L. Martin and M. Gorman and S. Hodgson and {De Polanco}, M.M.E. and M. Sans and A. Carracedo and S. Castellvi-Bel and A. Rojas-Martinez and E. Santos and M.R. Teixeira and L. Carvajal-Carmona and X.O. Shu and J. Long and W. Zheng and Y.B. Xiang and G.W. Montgomery and P.M. Webb and R.J. Scott and M. Mcevoy and J. Attia and E. Holliday and N.G. Martin and D.R. Nyholt and A.K. Henders and P.A. Fasching and A. Hein and M.W. Beckmann and S.P. Renner and T. D{\"o}rk and P. Hillemanns and M. D{\"u}rst and I. Runnebaum and D. Lambrechts and L. Coenegrachts and S. Schrauwen and F. Amant and B. Winterhoff and S.C. Dowdy and E.L. Goode and A. Teoman and H.B. Salvesen and J. Trovik and T.S. Njolstad and H.M.J. Werner and K. Ashton and T. Proietto and G. Otton and G. Tzortzatos and M. Mints and E. Tham and P. Hall and K. Czene and J. Liu and J. Li and J.L. Hopper and M.C. Southey and A.B. Ekici and M. Ruebner and N. Johnson and Yee Leung and J. Peto and B. Burwinkel and F. Marme and H. Brenner and A.K. Dieffenbach",
    year = "2015",
    doi = "10.1093/hmg/ddu552",
    language = "English",
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    pages = "1478--1492",
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    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, De Polanco, MME, 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, 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, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Leung, Y, Peto, J, Burwinkel, B, Marme, F, Brenner, H & Dieffenbach, AK 2015, 'Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk' Human Molecular Genetics, vol. 24, no. 5, pp. 1478-1492. https://doi.org/10.1093/hmg/ddu552

    Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. / Painter, J.N.; O'Mara, T.A.; Batra, J.; Cheng, T.; Lose, F.A.; Dennis, J.; Michailidou, K.; Tyrer, J.P.; Ahmed, S.; Ferguson, K.; Healey, C.S.; Kaufmann, S.; Hillman, K.M.; Walpole, C.; Moya, L.; Pollock, P.; Jones, A.; Howarth, K.; Martin, L.; Gorman, M.; Hodgson, S.; De Polanco, M.M.E.; Sans, M.; Carracedo, A.; Castellvi-Bel, S.; Rojas-Martinez, A.; Santos, E.; Teixeira, M.R.; Carvajal-Carmona, L.; Shu, X.O.; Long, J.; Zheng, W.; Xiang, Y.B.; Montgomery, G.W.; Webb, P.M.; Scott, R.J.; Mcevoy, M.; Attia, J.; Holliday, E.; Martin, N.G.; Nyholt, D.R.; Henders, A.K.; Fasching, P.A.; Hein, A.; Beckmann, M.W.; Renner, S.P.; Dörk, T.; Hillemanns, P.; Dürst, M.; Runnebaum, I.; Lambrechts, D.; Coenegrachts, L.; Schrauwen, S.; Amant, F.; Winterhoff, B.; Dowdy, S.C.; Goode, E.L.; Teoman, A.; Salvesen, H.B.; Trovik, J.; Njolstad, T.S.; Werner, H.M.J.; Ashton, K.; Proietto, T.; Otton, G.; Tzortzatos, G.; Mints, M.; Tham, E.; Hall, P.; Czene, K.; Liu, J.; Li, J.; Hopper, J.L.; Southey, M.C.; Ekici, A.B.; Ruebner, M.; Johnson, N.; Leung, Yee; Peto, J.; Burwinkel, B.; Marme, F.; Brenner, H.; Dieffenbach, A.K.

    In: Human Molecular Genetics, Vol. 24, No. 5, 2015, p. 1478-1492.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

    AU - Painter, J.N.

    AU - O'Mara, T.A.

    AU - Batra, J.

    AU - Cheng, T.

    AU - Lose, F.A.

    AU - Dennis, J.

    AU - Michailidou, K.

    AU - Tyrer, J.P.

    AU - Ahmed, S.

    AU - Ferguson, K.

    AU - Healey, C.S.

    AU - Kaufmann, S.

    AU - Hillman, K.M.

    AU - Walpole, C.

    AU - Moya, L.

    AU - Pollock, P.

    AU - Jones, A.

    AU - Howarth, K.

    AU - Martin, L.

    AU - Gorman, M.

    AU - Hodgson, S.

    AU - De Polanco, M.M.E.

    AU - Sans, M.

    AU - Carracedo, A.

    AU - Castellvi-Bel, S.

    AU - Rojas-Martinez, A.

    AU - Santos, E.

    AU - Teixeira, M.R.

    AU - Carvajal-Carmona, L.

    AU - Shu, X.O.

    AU - Long, J.

    AU - Zheng, W.

    AU - Xiang, Y.B.

    AU - Montgomery, G.W.

    AU - Webb, P.M.

    AU - Scott, R.J.

    AU - Mcevoy, M.

    AU - Attia, J.

    AU - Holliday, E.

    AU - Martin, N.G.

    AU - Nyholt, D.R.

    AU - Henders, A.K.

    AU - Fasching, P.A.

    AU - Hein, A.

    AU - Beckmann, M.W.

    AU - Renner, S.P.

    AU - Dörk, T.

    AU - Hillemanns, P.

    AU - Dürst, M.

    AU - Runnebaum, I.

    AU - Lambrechts, D.

    AU - Coenegrachts, L.

    AU - Schrauwen, S.

    AU - Amant, F.

    AU - Winterhoff, B.

    AU - Dowdy, S.C.

    AU - Goode, E.L.

    AU - Teoman, A.

    AU - Salvesen, H.B.

    AU - Trovik, J.

    AU - Njolstad, T.S.

    AU - Werner, H.M.J.

    AU - Ashton, K.

    AU - Proietto, T.

    AU - Otton, G.

    AU - Tzortzatos, G.

    AU - Mints, M.

    AU - Tham, E.

    AU - Hall, P.

    AU - Czene, K.

    AU - Liu, J.

    AU - Li, J.

    AU - Hopper, J.L.

    AU - Southey, M.C.

    AU - Ekici, A.B.

    AU - Ruebner, M.

    AU - Johnson, N.

    AU - Leung, Yee

    AU - Peto, J.

    AU - Burwinkel, B.

    AU - Marme, F.

    AU - Brenner, H.

    AU - Dieffenbach, A.K.

    PY - 2015

    Y1 - 2015

    N2 - © The Author 2014. 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.

    AB - © The Author 2014. 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.

    U2 - 10.1093/hmg/ddu552

    DO - 10.1093/hmg/ddu552

    M3 - Article

    VL - 24

    SP - 1478

    EP - 1492

    JO - Human Molecular Genetics

    JF - Human Molecular Genetics

    SN - 0964-6906

    IS - 5

    ER -