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

Timothy Ht 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 M Webb; John Attia; Elizabeth G Holliday; Mark McEvoy; Rodney J Scott; Anjali K Henders; 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; National Study of Endometrial Cancer Genetics Group (NSECG); Ian Tomlinson

doi:10.1038/ng.3562

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

Timothy Ht 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 M Webb, John Attia, Elizabeth G Holliday, Mark McEvoy, Rodney J Scott, Anjali K Henders, 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, National Study of Endometrial Cancer Genetics Group (NSECG), Ian Tomlinson

Cancer and Genomic Sciences

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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
Pages (from-to)	667-674
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	6
Early online date	2 May 2016
DOIs	https://doi.org/10.1038/ng.3562
Publication status	Published - Jun 2016

Keywords

Chromosomes, Human, Pair 8
Endometrial Neoplasms
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Journal Article
Meta-Analysis

UN SDGs

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

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10.1038/ng.3562

Tomlinson et al, Five endometrial cancer risk loci identified through genome-wide association analysis.
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Cheng, T. H., 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., Webb, P. M., Attia, J., Holliday, E. G., McEvoy, M., Scott, R. J., Henders, A. K., ... Tomlinson, I. (2016). Five endometrial cancer risk loci identified through genome-wide association analysis. Nature Genetics, 48(6), 667-674. Advance online publication. https://doi.org/10.1038/ng.3562

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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.",

keywords = "Chromosomes, Human, Pair 8, Endometrial Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Journal Article, Meta-Analysis",

author = "Cheng, {Timothy Ht} 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 Webb, {Penelope M} and John Attia and Holliday, {Elizabeth G} and Mark McEvoy and Scott, {Rodney J} and Henders, {Anjali K} 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 {National Study of Endometrial Cancer Genetics Group (NSECG)} and Ian Tomlinson",

year = "2016",

month = jun,

doi = "10.1038/ng.3562",

language = "English",

volume = "48",

pages = "667--674",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

Cheng, TH, 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, Webb, PM, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Henders, AK, 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, National Study of Endometrial Cancer Genetics Group (NSECG) & Tomlinson, I 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

TY - JOUR

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

AU - Cheng, Timothy Ht

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 - Webb, Penelope M

AU - Attia, John

AU - Holliday, Elizabeth G

AU - McEvoy, Mark

AU - Scott, Rodney J

AU - Henders, Anjali K

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 - National Study of Endometrial Cancer Genetics Group (NSECG)

AU - Tomlinson, Ian

PY - 2016/6

Y1 - 2016/6

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.

KW - Chromosomes, Human, Pair 8

KW - Endometrial Neoplasms

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Journal Article

KW - Meta-Analysis

U2 - 10.1038/ng.3562

DO - 10.1038/ng.3562

M3 - Article

C2 - 27135401

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

Abstract

Keywords

UN SDGs

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