Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Tracy A. O'Mara; Dylan M. Glubb; Jodie N. Painter; Timothy Cheng; Joe Dennis; John Attia; Elizabeth G. Holliday; Mark McEvoy; Rodney J. Scott; Katie Ashton; Tony Proietto; Geoffrey Otton; Mitul Shah; Shahana Ahmed; Catherine S. Healey; Maggie Gorman; Lynn Martin; Shirley Hodgson; Peter A. Fasching; Alexander Hein; Matthias W. Beckmann; Arif B. Ekici; Per Hall; Kamila Czene; Hatef Darabi; Jingmei Li; Matthias Dürst; Ingo Runnebaum; Peter Hillemanns; Thilo Dörk; Diether Lambrechts; Jeroen Depreeuw; Daniela Annibali; Frederic Amant; Hui Zhao; Ellen L. Goode; Sean C. Dowdy; Brooke L. Fridley; Stacey J. Winham; Helga B. Salvesen; Tormund S. Njølstad; Jone Trovik; Henrica M. J. Werner; Emma Tham; Tao Liu; Miriam Mints; Manjeet K. Bolla; Kyriaki Michailidou; Jonathan P. Tyrer; Qin Wang; 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; Paul D. P. Pharoah; Alison M. Dunning; Ian Tomlinson; Douglas F. Easton; Deborah J. Thompson; Amanda B. Spurdle

doi:https://doi.org/10.1530/ERC-15-0319

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Tracy A. O'Mara, Dylan M. Glubb, Jodie N. Painter, Timothy Cheng, Joe Dennis, John Attia, Elizabeth G. Holliday, Mark McEvoy, Rodney J. Scott, Katie Ashton, Tony Proietto, Geoffrey Otton, Mitul Shah, Shahana Ahmed, Catherine S. Healey, Maggie Gorman, Lynn Martin, Shirley Hodgson, Peter A. Fasching, Alexander HeinMatthias W. Beckmann, Arif B. Ekici, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Matthias Dürst, Ingo Runnebaum, Peter Hillemanns, Thilo Dörk, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Hui Zhao, Ellen L. Goode, Sean C. Dowdy, Brooke L. Fridley, Stacey J. Winham, Helga B. Salvesen, Tormund S. Njølstad, Jone Trovik, Henrica M. J. Werner, Emma Tham, Tao Liu, Miriam Mints, Manjeet K. Bolla, Kyriaki Michailidou, Jonathan P. Tyrer, Qin Wang, 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, Paul D. P. Pharoah, Alison M. Dunning, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, Amanda B. Spurdle

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

23 Citations (Scopus)

Abstract

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86x10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76x10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types

Original language	English
Pages (from-to)	851-861
Journal	Endocrine-related cancer
Volume	22
Issue number	5
DOIs	https://doi.org/10.1530/ERC-15-0319
Publication status	Published - 2015

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https://doi.org/10.1530/ERC-15-0319

Cite this

O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Dennis, J., Attia, J., Holliday, E. G., McEvoy, M., Scott, R. J., Ashton, K., Proietto, T., Otton, G., Shah, M., Ahmed, S., Healey, C. S., Gorman, M., Martin, L., Hodgson, S., Fasching, P. A., ... Spurdle, A. B. (2015). Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer. Endocrine-related cancer, 22(5), 851-861. https://doi.org/10.1530/ERC-15-0319

@article{d55865028dd743c7babdb72a34c4bcee,

title = "Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer",

abstract = "Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86x10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76x10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types",

author = "O'Mara, {Tracy A.} and Glubb, {Dylan M.} and Painter, {Jodie N.} and Timothy Cheng and Joe Dennis and John Attia and Holliday, {Elizabeth G.} and Mark McEvoy and Scott, {Rodney J.} and Katie Ashton and Tony Proietto and Geoffrey Otton and Mitul Shah and Shahana Ahmed and Healey, {Catherine S.} and Maggie Gorman and Lynn Martin and Shirley Hodgson and Fasching, {Peter A.} and Alexander Hein and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Per Hall and Kamila Czene and Hatef Darabi and Jingmei Li and Matthias D{\"u}rst and Ingo Runnebaum and Peter Hillemanns and Thilo D{\"o}rk and Diether Lambrechts and Jeroen Depreeuw and Daniela Annibali and Frederic Amant and Hui Zhao and Goode, {Ellen L.} and Dowdy, {Sean C.} and Fridley, {Brooke L.} and Winham, {Stacey J.} and Salvesen, {Helga B.} and Nj{\o}lstad, {Tormund S.} and Jone Trovik and Werner, {Henrica M. J.} and Emma Tham and Tao Liu and Miriam Mints and Bolla, {Manjeet K.} and Kyriaki Michailidou and Tyrer, {Jonathan P.} and Qin Wang 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 Pharoah, {Paul D. P.} and Dunning, {Alison M.} and Ian Tomlinson and Easton, {Douglas F.} and Thompson, {Deborah J.} and Spurdle, {Amanda B.}",

year = "2015",

doi = "https://doi.org/10.1530/ERC-15-0319",

language = "English",

volume = "22",

pages = "851--861",

journal = "Endocrine-related cancer",

issn = "1351-0088",

publisher = "Society for Endocrinology",

number = "5",

}

O'Mara, TA, Glubb, DM, Painter, JN, Cheng, T, Dennis, J, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Shah, M, Ahmed, S, Healey, CS, Gorman, M, Martin, L, Hodgson, S, Fasching, PA, Hein, A, Beckmann, MW, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Dürst, M, Runnebaum, I, Hillemanns, P, Dörk, T, Lambrechts, D, Depreeuw, J, Annibali, D, Amant, F, Zhao, H, Goode, EL, Dowdy, SC, Fridley, BL, Winham, SJ, Salvesen, HB, Njølstad, TS, Trovik, J, Werner, HMJ, Tham, E, Liu, T, Mints, M, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, 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, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Thompson, DJ & Spurdle, AB 2015, 'Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer', Endocrine-related cancer, vol. 22, no. 5, pp. 851-861. https://doi.org/10.1530/ERC-15-0319

TY - JOUR

T1 - Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

AU - O'Mara, Tracy A.

AU - Glubb, Dylan M.

AU - Painter, Jodie N.

AU - Cheng, Timothy

AU - Dennis, Joe

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - McEvoy, Mark

AU - Scott, Rodney J.

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Shah, Mitul

AU - Ahmed, Shahana

AU - Healey, Catherine S.

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Hodgson, Shirley

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Hall, Per

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Hillemanns, Peter

AU - Dörk, Thilo

AU - Lambrechts, Diether

AU - Depreeuw, Jeroen

AU - Annibali, Daniela

AU - Amant, Frederic

AU - Zhao, Hui

AU - Goode, Ellen L.

AU - Dowdy, Sean C.

AU - Fridley, Brooke L.

AU - Winham, Stacey J.

AU - Salvesen, Helga B.

AU - Njølstad, Tormund S.

AU - Trovik, Jone

AU - Werner, Henrica M. J.

AU - Tham, Emma

AU - Liu, Tao

AU - Mints, Miriam

AU - Bolla, Manjeet K.

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P.

AU - Wang, Qin

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 - Pharoah, Paul D. P.

AU - Dunning, Alison M.

AU - Tomlinson, Ian

AU - Easton, Douglas F.

AU - Thompson, Deborah J.

AU - Spurdle, Amanda B.

PY - 2015

Y1 - 2015

N2 - Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86x10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76x10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types

AB - Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86x10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76x10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types

U2 - https://doi.org/10.1530/ERC-15-0319

DO - https://doi.org/10.1530/ERC-15-0319

M3 - Article

C2 - 26330482

SN - 1351-0088

VL - 22

SP - 851

EP - 861

JO - Endocrine-related cancer

JF - Endocrine-related cancer

IS - 5

ER -