Five endometrial cancer risk loci identified through genome-wide association analysis

Timothy H.T. Cheng; Deborah J. Thompson; Tracy A. O'Mara; Jodie N. Painter; Dylan M. Glubb; Susanne Flach; Annabelle Lewis; Juliet D. French; Luke Freeman-Mills; David Church; Maggie Gorman; Lynn Martin; Shirley Hodgson; Penelope MWebb; John Attia; Elizabeth G. Holliday; Mark McEvoy; Rodney J. Scott; Anjali KHenders; Nicholas G. Martin; Grant W. Montgomery; Dale R. Nyholt; Shahana Ahmed; Catherine S. Healey; Mitul Shah; Joe Dennis; Peter A. Fasching; Matthias W. Beckmann; Alexander Hein; Arif B. Ekici; Per Hall; Kamila Czene; Hatef Darabi; Jingmei Li; Thilo Dörk; Matthias Dürst; Peter Hillemanns; Ingo Runnebaum; Frederic Amant; Stefanie Schrauwen; Hui Zhao; Diether Lambrechts; Jeroen Depreeuw; Sean C. Dowdy; Ellen L. Goode; Brooke L. Fridley; Stacey J. Winham; Tormund S. NjØlstad; Helga B. Salvesen; Jone Trovik; Henrica M.J. Werner; Katie Ashton; Geoffrey Otton; Tony Proietto; Tao Liu; Miriam Mints; Emma Tham; Mulin Jun Li; Shun H. Yip; Junwen Wang; Manjeet KBolla; Kyriaki Michailidou; Qin Wang; Jonathan P. Tyrer; Malcolm Dunlop; Richard Houlston; Claire Palles; John L. Hopper; Julian Peto; Anthony J. Swerdlow; Barbara Burwinkel; Hermann Brenner; Alfons Meindl; Hiltrud Brauch; Annika Lindblom; Jenny Chang-Claude; Fergus J. Couch; Graham G. Giles; Vessela N. Kristensen; Angela Cox; Julie MCunningham; Paul D.P. Pharoah; Alison M. Dunning; Stacey L. Edwards; Douglas F. Easton; Ian Tomlinson; Amanda B. Spurdle

doi:10.1038/ng.3562

Five endometrial cancer risk loci identified through genome-wide association analysis

Timothy H.T. Cheng, Deborah J. Thompson, Tracy A. O'Mara, Jodie N. Painter, Dylan M. Glubb, Susanne Flach, Annabelle Lewis, Juliet D. French, Luke Freeman-Mills, David Church, Maggie Gorman, Lynn Martin, Shirley Hodgson, Penelope MWebb, John Attia, Elizabeth G. Holliday, Mark McEvoy, Rodney J. Scott, Anjali KHenders, Nicholas G. MartinGrant W. Montgomery, Dale R. Nyholt, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Joe Dennis, Peter A. Fasching, Matthias W. Beckmann, Alexander Hein, Arif B. Ekici, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Frederic Amant, Stefanie Schrauwen, Hui Zhao, Diether Lambrechts, Jeroen Depreeuw, Sean C. Dowdy, Ellen L. Goode, Brooke L. Fridley, Stacey J. Winham, Tormund S. NjØlstad, Helga B. Salvesen, Jone Trovik, Henrica M.J. Werner, Katie Ashton, Geoffrey Otton, Tony Proietto, Tao Liu, Miriam Mints, Emma Tham, Mulin Jun Li, Shun H. Yip, Junwen Wang, Manjeet KBolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, Malcolm Dunlop, Richard Houlston, Claire Palles, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang-Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Julie MCunningham, Paul D.P. Pharoah, Alison M. Dunning, Stacey L. Edwards, Douglas F. Easton, Ian Tomlinson, Amanda B. Spurdle

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Abstract

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Original language	English (US)
Pages (from-to)	667-674
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	6
DOIs	https://doi.org/10.1038/ng.3562
State	Published - Jun 1 2016

ASJC Scopus subject areas

Genetics

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Cheng, T. H. T., Thompson, D. J., O'Mara, T. A., Painter, J. N., Glubb, D. M., Flach, S., Lewis, A., French, J. D., Freeman-Mills, L., Church, D., Gorman, M., Martin, L., Hodgson, S., MWebb, P., Attia, J., Holliday, E. G., McEvoy, M., Scott, R. J., KHenders, A., ... Spurdle, A. B. (2016). Five endometrial cancer risk loci identified through genome-wide association analysis. Nature Genetics, 48(6), 667-674. https://doi.org/10.1038/ng.3562

Cheng, THT, Thompson, DJ, O'Mara, TA, Painter, JN, Glubb, DM, Flach, S, Lewis, A, French, JD, Freeman-Mills, L, Church, D, Gorman, M, Martin, L, Hodgson, S, MWebb, P, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, KHenders, A, Martin, NG, Montgomery, GW, Nyholt, DR, Ahmed, S, Healey, CS, Shah, M, Dennis, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, I, Amant, F, Schrauwen, S, Zhao, H, Lambrechts, D, Depreeuw, J, Dowdy, SC , Goode, EL, Fridley, BL, Winham, SJ, NjØlstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, K, Otton, G, Proietto, T, Liu, T, Mints, M, Tham, E, Li, MJ, Yip, SH, Wang, J, KBolla, M, Michailidou, K, Wang, Q, Tyrer, JP, Dunlop, M, Houlston, R, Palles, C, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, MCunningham, J, Pharoah, PDP, Dunning, AM, Edwards, SL, Easton, DF, Tomlinson, I & Spurdle, AB 2016, 'Five endometrial cancer risk loci identified through genome-wide association analysis', Nature Genetics, vol. 48, no. 6, pp. 667-674. https://doi.org/10.1038/ng.3562

@article{480b56859dff4a15aa34b7554eb4249a,

title = "Five endometrial cancer risk loci identified through genome-wide association analysis",

abstract = "We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.",

author = "Cheng, {Timothy H.T.} and Thompson, {Deborah J.} and O'Mara, {Tracy A.} and Painter, {Jodie N.} and Glubb, {Dylan M.} and Susanne Flach and Annabelle Lewis and French, {Juliet D.} and Luke Freeman-Mills and David Church and Maggie Gorman and Lynn Martin and Shirley Hodgson and Penelope MWebb and John Attia and Holliday, {Elizabeth G.} and Mark McEvoy and Scott, {Rodney J.} and Anjali KHenders and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Nyholt, {Dale R.} and Shahana Ahmed and Healey, {Catherine S.} and Mitul Shah and Joe Dennis and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Alexander Hein and Ekici, {Arif B.} and Per Hall and Kamila Czene and Hatef Darabi and Jingmei Li and Thilo D{\"o}rk and Matthias D{\"u}rst and Peter Hillemanns and Ingo Runnebaum and Frederic Amant and Stefanie Schrauwen and Hui Zhao and Diether Lambrechts and Jeroen Depreeuw and Dowdy, {Sean C.} and Goode, {Ellen L.} and Fridley, {Brooke L.} and Winham, {Stacey J.} and Nj{\O}lstad, {Tormund S.} and Salvesen, {Helga B.} and Jone Trovik and Werner, {Henrica M.J.} and Katie Ashton and Geoffrey Otton and Tony Proietto and Tao Liu and Miriam Mints and Emma Tham and Li, {Mulin Jun} and Yip, {Shun H.} and Junwen Wang and Manjeet KBolla and Kyriaki Michailidou and Qin Wang and Tyrer, {Jonathan P.} and Malcolm Dunlop and Richard Houlston and Claire Palles and Hopper, {John L.} and Julian Peto and Swerdlow, {Anthony J.} and Barbara Burwinkel and Hermann Brenner and Alfons Meindl and Hiltrud Brauch and Annika Lindblom and Jenny Chang-Claude and Couch, {Fergus J.} and Giles, {Graham G.} and Kristensen, {Vessela N.} and Angela Cox and Julie MCunningham and Pharoah, {Paul D.P.} and Dunning, {Alison M.} and Edwards, {Stacey L.} and Easton, {Douglas F.} and Ian Tomlinson and Spurdle, {Amanda B.}",

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = jun,

day = "1",

doi = "10.1038/ng.3562",

language = "English (US)",

volume = "48",

pages = "667--674",

journal = "Nature Genetics",

issn = "1061-4036",

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number = "6",

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TY - JOUR

T1 - Five endometrial cancer risk loci identified through genome-wide association analysis

AU - Cheng, Timothy H.T.

AU - Thompson, Deborah J.

AU - O'Mara, Tracy A.

AU - Painter, Jodie N.

AU - Glubb, Dylan M.

AU - Flach, Susanne

AU - Lewis, Annabelle

AU - French, Juliet D.

AU - Freeman-Mills, Luke

AU - Church, David

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Hodgson, Shirley

AU - MWebb, Penelope

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - McEvoy, Mark

AU - Scott, Rodney J.

AU - KHenders, Anjali

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Nyholt, Dale R.

AU - Ahmed, Shahana

AU - Healey, Catherine S.

AU - Shah, Mitul

AU - Dennis, Joe

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Hall, Per

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Dörk, Thilo

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Runnebaum, Ingo

AU - Amant, Frederic

AU - Schrauwen, Stefanie

AU - Zhao, Hui

AU - Lambrechts, Diether

AU - Depreeuw, Jeroen

AU - Dowdy, Sean C.

AU - Goode, Ellen L.

AU - Fridley, Brooke L.

AU - Winham, Stacey J.

AU - NjØlstad, Tormund S.

AU - Salvesen, Helga B.

AU - Trovik, Jone

AU - Werner, Henrica M.J.

AU - Ashton, Katie

AU - Otton, Geoffrey

AU - Proietto, Tony

AU - Liu, Tao

AU - Mints, Miriam

AU - Tham, Emma

AU - Li, Mulin Jun

AU - Yip, Shun H.

AU - Wang, Junwen

AU - KBolla, Manjeet

AU - Michailidou, Kyriaki

AU - Wang, Qin

AU - Tyrer, Jonathan P.

AU - Dunlop, Malcolm

AU - Houlston, Richard

AU - Palles, Claire

AU - Hopper, John L.

AU - Peto, Julian

AU - Swerdlow, Anthony J.

AU - Burwinkel, Barbara

AU - Brenner, Hermann

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - Lindblom, Annika

AU - Chang-Claude, Jenny

AU - Couch, Fergus J.

AU - Giles, Graham G.

AU - Kristensen, Vessela N.

AU - Cox, Angela

AU - MCunningham, Julie

AU - Pharoah, Paul D.P.

AU - Dunning, Alison M.

AU - Edwards, Stacey L.

AU - Easton, Douglas F.

AU - Tomlinson, Ian

AU - Spurdle, Amanda B.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

AB - We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

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U2 - 10.1038/ng.3562

DO - 10.1038/ng.3562

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SP - 667

EP - 674

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Five endometrial cancer risk loci identified through genome-wide association analysis

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