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

Jodie N. Painter; Tracy A. O'Mara; Jyotsna Batra; Timothy Cheng; Felicity A. Lose; Joe Dennis; Kyriaki Michailidou; Jonathan P. Tyrer; Shahana Ahmed; Kaltin Ferguson; Catherine S. Healey; Susanne Kaufmann; Kristine M. Hillman; Carina Walpole; Leire Moya; Pamela Pollock; Angela Jones; Kimberley Howarth; Lynn Martin; Maggie Gorman; Shirley Hodgson; Ma Magdalena Echeverry De Polanco; Monica Sans; Angel Carracedo; Sergi Castellvi-Bel; Augusto Rojas-Martinez; Erika Santos; Manuel R. Teixeira; Luis Carvajal-Carmona; Xiao Ou Shu; Jirong Long; Wei Zheng; Yong Bing Xiang; Grant W. Montgomery; Penelope M. Webb; Rodney J. Scott; Mark McEvoy; John Attia; Elizabeth Holliday; Nicholas G. Martin; Dale R. Nyholt; Anjali K. Henders; Peter A. Fasching; Alexander Hein; Matthias W. Beckmann; Stefan P. Renner; Thilo Dörk; Peter Hillemanns; Matthias Dürst; Ingo Runnebaum; Diether Lambrechts; Lieve Coenegrachts; Stefanie Schrauwen; Frederic Amant; Boris Winterhoff; Sean C. Dowdy; Ellen L. Goode; Attila Teoman; Helga B. Salvesen; Jone Trovik; Tormund S. Njolstad; Henrica M J Werner; Katie Ashton; Tony Proietto; Geoffrey Otton; Gerasimos Tzortzatos; Miriam Mints; Emma Tham; Per Hall; Kamila Czene; Jianjun Liu; Jingmei Li; John L. Hopper; Melissa C. Southey; Arif B. Ekici; Matthias Ruebner; Nicola Johnson; Julian Peto; Barbara Burwinkel; Frederik Marme; Hermann Brenner; Aida K. Dieffenbach; Alfons Meindl; Hiltrud Brauch; Annika Lindblom; Jeroen Depreeuw; Matthieu Moisse; Jenny Chang-Claude; Anja Rudolph; Fergus J. Couch; Janet E. Olson; Graham G. Giles; Fiona Bruinsma; Julie M. Cunningham; Brooke L. Fridley; Anne Lise Børresen-Dale; Vessela N. Kristensen; Angela Cox; Anthony J. Swerdlow; Nicholas Orr; Manjeet K. Bolla; Qin Wang; Rachel Palmieri Weber; Zhihua Chen; Mitul Shah; Juliet D. French; Paul D P Pharoah; Alison M. Dunning; Ian Tomlinson; Douglas F. Easton; Stacey L. Edwards; Deborah J. Thompson; Amanda B. Spurdle

doi:10.1093/hmg/ddu552

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

Jodie N. Painter, Tracy A. O'Mara, Jyotsna Batra, Timothy Cheng, Felicity A. Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P. Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S. Healey, Susanne Kaufmann, Kristine M. Hillman, Carina Walpole, Leire Moya, Pamela Pollock, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie GormanShirley Hodgson, Ma Magdalena Echeverry De Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Erika Santos, Manuel R. Teixeira, Luis Carvajal-Carmona, Xiao Ou Shu, Jirong Long, Wei Zheng, Yong Bing Xiang, Grant W. Montgomery, Penelope M. Webb, Rodney J. Scott, Mark McEvoy, John Attia, Elizabeth Holliday, Nicholas G. Martin, Dale R. Nyholt, Anjali K. Henders, Peter A. Fasching, Alexander Hein, Matthias W. Beckmann, Stefan P. Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic Amant, Boris Winterhoff, Sean C. Dowdy, Ellen L. Goode, Attila Teoman, Helga B. Salvesen, Jone Trovik, Tormund S. Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L. Hopper, Melissa C. Southey, Arif B. Ekici, Matthias Ruebner, Nicola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K. Dieffenbach, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Fiona Bruinsma, Julie M. Cunningham, Brooke L. Fridley, Anne Lise Børresen-Dale, Vessela N. Kristensen, Angela Cox, Anthony J. Swerdlow, Nicholas Orr, Manjeet K. Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Juliet D. French, Paul D P Pharoah, Alison M. Dunning, Ian Tomlinson, Douglas F. Easton, Stacey L. Edwards, Deborah J. Thompson, Amanda B. Spurdle

Obstetrics, Gynecology and Women's Health - Oncology

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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 language	English (US)
Pages (from-to)	1478-1492
Number of pages	15
Journal	Human molecular genetics
Volume	24
Issue number	5
DOIs	https://doi.org/10.1093/hmg/ddu552
State	Published - Mar 1 2015

Bibliographical note

Publisher Copyright:
© The Author 2014.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., ... Spurdle, A. B. (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, 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, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, 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, PDP, 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, vol. 24, no. 5, pp. 1478-1492. https://doi.org/10.1093/hmg/ddu552

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

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 = "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 and Diether Lambrechts and Lieve Coenegrachts and Stefanie Schrauwen and Frederic Amant and Boris Winterhoff and Dowdy, {Sean C.} and Goode, {Ellen L.} and Attila Teoman and Salvesen, {Helga B.} and Jone Trovik and Njolstad, {Tormund S.} and Werner, {Henrica M J} and Katie Ashton and Tony Proietto and Geoffrey Otton and Gerasimos Tzortzatos and Miriam Mints and Emma Tham and Per Hall and Kamila Czene and Jianjun Liu and Jingmei Li and Hopper, {John L.} and Southey, {Melissa C.} and Ekici, {Arif B.} and Matthias Ruebner and Nicola Johnson and Julian Peto and Barbara Burwinkel and Frederik Marme and Hermann Brenner and Dieffenbach, {Aida K.} and Alfons Meindl and Hiltrud Brauch and Annika Lindblom and Jeroen Depreeuw and Matthieu Moisse and Jenny Chang-Claude and Anja Rudolph and Couch, {Fergus J.} and Olson, {Janet E.} and Giles, {Graham G.} and Fiona Bruinsma and Cunningham, {Julie M.} and Fridley, {Brooke L.} and B{\o}rresen-Dale, {Anne Lise} and Kristensen, {Vessela N.} and Angela Cox and Swerdlow, {Anthony J.} and Nicholas Orr and Bolla, {Manjeet K.} and Qin Wang and Weber, {Rachel Palmieri} and Zhihua Chen and Mitul Shah and French, {Juliet D.} and Pharoah, {Paul D P} and Dunning, {Alison M.} and Ian Tomlinson and Easton, {Douglas F.} and Edwards, {Stacey L.} and Thompson, {Deborah J.} and Spurdle, {Amanda B.}",

note = "Publisher Copyright: {\textcopyright} The Author 2014.",

year = "2015",

month = mar,

day = "1",

doi = "10.1093/hmg/ddu552",

language = "English (US)",

volume = "24",

pages = "1478--1492",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "5",

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TY - JOUR

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

AU - Painter, Jodie N.

AU - O'Mara, Tracy A.

AU - Batra, Jyotsna

AU - Cheng, Timothy

AU - Lose, Felicity A.

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P.

AU - Ahmed, Shahana

AU - Ferguson, Kaltin

AU - Healey, Catherine S.

AU - Kaufmann, Susanne

AU - Hillman, Kristine M.

AU - Walpole, Carina

AU - Moya, Leire

AU - Pollock, Pamela

AU - Jones, Angela

AU - Howarth, Kimberley

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Hodgson, Shirley

AU - De Polanco, Ma Magdalena Echeverry

AU - Sans, Monica

AU - Carracedo, Angel

AU - Castellvi-Bel, Sergi

AU - Rojas-Martinez, Augusto

AU - Santos, Erika

AU - Teixeira, Manuel R.

AU - Carvajal-Carmona, Luis

AU - Shu, Xiao Ou

AU - Long, Jirong

AU - Zheng, Wei

AU - Xiang, Yong Bing

AU - Montgomery, Grant W.

AU - Webb, Penelope M.

AU - Scott, Rodney J.

AU - McEvoy, Mark

AU - Attia, John

AU - Holliday, Elizabeth

AU - Martin, Nicholas G.

AU - Nyholt, Dale R.

AU - Henders, Anjali K.

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Beckmann, Matthias W.

AU - Renner, Stefan P.

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Lambrechts, Diether

AU - Coenegrachts, Lieve

AU - Schrauwen, Stefanie

AU - Amant, Frederic

AU - Winterhoff, Boris

AU - Dowdy, Sean C.

AU - Goode, Ellen L.

AU - Teoman, Attila

AU - Salvesen, Helga B.

AU - Trovik, Jone

AU - Njolstad, Tormund S.

AU - Werner, Henrica M J

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Tzortzatos, Gerasimos

AU - Mints, Miriam

AU - Tham, Emma

AU - Hall, Per

AU - Czene, Kamila

AU - Liu, Jianjun

AU - Li, Jingmei

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Ekici, Arif B.

AU - Ruebner, Matthias

AU - Johnson, Nicola

AU - Peto, Julian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Brenner, Hermann

AU - Dieffenbach, Aida K.

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - Lindblom, Annika

AU - Depreeuw, Jeroen

AU - Moisse, Matthieu

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Cunningham, Julie M.

AU - Fridley, Brooke L.

AU - Børresen-Dale, Anne Lise

AU - Kristensen, Vessela N.

AU - Cox, Angela

AU - Swerdlow, Anthony J.

AU - Orr, Nicholas

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Weber, Rachel Palmieri

AU - Chen, Zhihua

AU - Shah, Mitul

AU - French, Juliet D.

AU - Pharoah, Paul D P

AU - Dunning, Alison M.

AU - Tomlinson, Ian

AU - Easton, Douglas F.

AU - Edwards, Stacey L.

AU - Thompson, Deborah J.

AU - Spurdle, Amanda B.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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 - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84924440664&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu552

DO - 10.1093/hmg/ddu552

M3 - Article

C2 - 25378557

AN - SCOPUS:84924440664

SN - 0964-6906

VL - 24

SP - 1478

EP - 1492

JO - Human molecular genetics

JF - Human molecular genetics

IS - 5

ER -

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

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