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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42 Scopus citations

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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10.1038/ng.3562

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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 = "Funding Information: The iCOGS endometrial cancer analysis was supported by an NHMRC project grant (1031333) to A.B.S., D.F.E. and A.M.D. A.B.S., P.M.W., G.W.M. and D.R.N. are supported by the NHMRC Fellowship scheme. A.M.D. was supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. T.H.T.C. is supported by the Rhodes Trust and the Nuffield Department of Medicine. Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065 and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. ANECS recruitment was supported by project grants from the NHMRC (339435), Cancer Council Queensland (4196615) and Cancer Council Tasmania (403031 and 457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. Recruitment of the QIMR Berghofer controls was supported by the NHMRC. The University of Newcastle, the Gladys M. Brawn Senior Research Fellowship scheme, the Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed toward the costs of establishing HCS. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Hannover-Jena Endometrial Cancer Study was partly supported by the Rudolf Bartling Foundation. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for Endometrial Cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of the US Public Health Service (R01 CA122443, P30 CA15083 and P50 CA136393), the Fred C. and Katherine B. Andersen Foundation, the Mayo Foundation and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, the Melzer Foundation, the Norwegian Cancer Society (Harald Andersens legat), the Research Council of Norway and Haukeland University Hospital. The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, the NBN Children's Cancer Research Group, Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141 and DF 07015), Swedish Labor Market Insurance (100069) and the Swedish Cancer Society (11 0439). The Cancer Hormone Replacement Epidemiology in Sweden study (CAHRES; formerly called the Singapore and Swedish Breast/Endometrial Cancer study, SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institutes of Health and the Susan G. Komen Breast Cancer Foundation. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. 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",

publisher = "Nature Publishing Group",

number = "6",

}

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.

N1 - Funding Information: The iCOGS endometrial cancer analysis was supported by an NHMRC project grant (1031333) to A.B.S., D.F.E. and A.M.D. A.B.S., P.M.W., G.W.M. and D.R.N. are supported by the NHMRC Fellowship scheme. A.M.D. was supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. T.H.T.C. is supported by the Rhodes Trust and the Nuffield Department of Medicine. Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065 and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. ANECS recruitment was supported by project grants from the NHMRC (339435), Cancer Council Queensland (4196615) and Cancer Council Tasmania (403031 and 457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. Recruitment of the QIMR Berghofer controls was supported by the NHMRC. The University of Newcastle, the Gladys M. Brawn Senior Research Fellowship scheme, the Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed toward the costs of establishing HCS. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Hannover-Jena Endometrial Cancer Study was partly supported by the Rudolf Bartling Foundation. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for Endometrial Cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of the US Public Health Service (R01 CA122443, P30 CA15083 and P50 CA136393), the Fred C. and Katherine B. Andersen Foundation, the Mayo Foundation and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, the Melzer Foundation, the Norwegian Cancer Society (Harald Andersens legat), the Research Council of Norway and Haukeland University Hospital. The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, the NBN Children's Cancer Research Group, Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141 and DF 07015), Swedish Labor Market Insurance (100069) and the Swedish Cancer Society (11 0439). The Cancer Hormone Replacement Epidemiology in Sweden study (CAHRES; formerly called the Singapore and Swedish Breast/Endometrial Cancer study, SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institutes of Health and the Susan G. Komen Breast Cancer Foundation. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Publisher Copyright: © 2016 Nature America, Inc.

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.

UR - http://www.scopus.com/inward/record.url?scp=84965053962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965053962&partnerID=8YFLogxK

U2 - 10.1038/ng.3562

DO - 10.1038/ng.3562

M3 - Article

C2 - 27135401

AN - SCOPUS:84965053962

SN - 1061-4036

VL - 48

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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