9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

Helen Warren; Frank Dudbridge; Olivia Fletcher; Nick Orr; Nichola Johnson; John L. Hopper; Carmel Apicella; Melissa C. Southey; Maryam Mahmoodi; Marjanka K. Schmidt; Annegien Broeks; Sten Cornelissen; Linda M. Braaf; Kenneth R. Muir; Artitaya Lophatananon; Arkom Chaiwerawattana; Surapon Wiangnon; Peter A. Fasching; Matthias W. Beckmann; Arif B. Ekici; Ruediger Schulz-Wendtland; Elinor J. Sawyer; Ian Tomlinson; Michael Kerin; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Pascal Guénel; Thérèse Truong; Pierre Laurent-Puig; Claire Mulot; Stig E. Bojesen; Sune F. Nielsen; Henrik Flyger; Børge G. Nordestgaard; Roger L. Milne; Javier Benítez; José Ignacio Arias-Pérez; M. Pilar Zamora; Hoda Anton-Culver; Argyrios Ziogas; Leslie Bernstein; Christina Clarke Dur; Hermann Brenner; Heiko Müller; Volker Arndt; Anne Langheinz; Alfons Meindl; Michael Golatta; Claus R. Bartram; Rita K. Schmutzler; Hiltrud Brauch; Christina Justenhoven; Thomas Brüning; Jenny Chang-Claude; Shan Wang-Gohrke; Ursula Eilber; Thilo Dörk; Peter Schürmann; Michael Bremer; Peter Hillemanns; Heli Nevanlinna; Taru A. Muranen; Kristiina Aittomäki; Carl Blomqvist; Natalia Bogdanova; Natalia Antonenkova; Yuriy Rogov; Marina Bermisheva; Darya Prokofyeva; Guzel Zinnatullina; Elza Khusnutdinova; Annika Lindblom; Sara Margolin; Arto Mannermaa; Veli Matti Kosma; Jaana M. Hartikainen; Vesa Kataja; Georgia Chenevix-Trench; Jonathan Beesley; Xiaoqing Chen; Diether Lambrechts; Ann Smeets; Robert Paridaens; Caroline Weltens; Dieter Flesch-Janys; Katharina Buck; Sabine Behrens; Paolo Peterlongo; Loris Bernard; Siranoush Manoukian; Paolo Radice; Fergus J. Couch; Celine Vachon; Xianshu Wang; Janet Olson; Graham Giles; Laura Baglietto; Cariona A. McLean; Gianluca Severi; Esther M. John; Alexander Miron; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Irene L. Andrulis; Julia A. Knight; Anna Marie Mulligan; Nayana Weerasooriya; Peter Devilee; Robert A.E.M. Tollenaar; John W.M. Martens; Caroline M. Seynaeve; Maartje J. Hooning; Antoinette Hollestelle; Agnes Jager; Madeleine M.A. Tilanus-Linthorst; Per Hall; Kamila Czene; Jianjun Liu; Jingmei Li; Angela Cox; Simon S. Cross; Ian W. Brock; Malcolm W.R. Reed; Paul Pharoah; Fiona M. Blows; Alison M. Dunning; Maya Ghoussaini; Alan Ashworth; Anthony Swerdlow; Michael Jones; Minouk Schoemaker; Douglas F. Easton; Manjeet Humphreys; Qin Wang; Julian Peto; Isabel Dos-Santos-Silva

doi:10.1158/1055-9965.EPI-12-0526

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

Helen Warren, Frank Dudbridge, Olivia Fletcher, Nick Orr, Nichola Johnson, John L. Hopper, Carmel Apicella, Melissa C. Southey, Maryam Mahmoodi, Marjanka K. Schmidt, Annegien Broeks, Sten Cornelissen, Linda M. Braaf, Kenneth R. Muir, Artitaya Lophatananon, Arkom Chaiwerawattana, Surapon Wiangnon, Peter A. Fasching, Matthias W. Beckmann, Arif B. EkiciRuediger Schulz-Wendtland, Elinor J. Sawyer, Ian Tomlinson, Michael Kerin, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Stig E. Bojesen, Sune F. Nielsen, Henrik Flyger, Børge G. Nordestgaard, Roger L. Milne, Javier Benítez, José Ignacio Arias-Pérez, M. Pilar Zamora, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Hermann Brenner, Heiko Müller, Volker Arndt, Anne Langheinz, Alfons Meindl, Michael Golatta, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Christina Justenhoven, Thomas Brüning, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Thilo Dörk, Peter Schürmann, Michael Bremer, Peter Hillemanns, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia Bogdanova, Natalia Antonenkova, Yuriy Rogov, Marina Bermisheva, Darya Prokofyeva, Guzel Zinnatullina, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli Matti Kosma, Jaana M. Hartikainen, Vesa Kataja, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Diether Lambrechts, Ann Smeets, Robert Paridaens, Caroline Weltens, Dieter Flesch-Janys, Katharina Buck, Sabine Behrens, Paolo Peterlongo, Loris Bernard, Siranoush Manoukian, Paolo Radice, Fergus J. Couch, Celine Vachon, Xianshu Wang, Janet Olson, Graham Giles, Laura Baglietto, Cariona A. McLean, Gianluca Severi, Esther M. John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Anna Marie Mulligan, Nayana Weerasooriya, Peter Devilee, Robert A.E.M. Tollenaar, John W.M. Martens, Caroline M. Seynaeve, Maartje J. Hooning, Antoinette Hollestelle, Agnes Jager, Madeleine M.A. Tilanus-Linthorst, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, Angela Cox, Simon S. Cross, Ian W. Brock, Malcolm W.R. Reed, Paul Pharoah, Fiona M. Blows, Alison M. Dunning, Maya Ghoussaini, Alan Ashworth, Anthony Swerdlow, Michael Jones, Minouk Schoemaker, Douglas F. Easton, Manjeet Humphreys, Qin Wang, Julian Peto, Isabel Dos-Santos-Silva

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

14 Scopus citations

Abstract

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype.

Original language	English (US)
Pages (from-to)	1783-1791
Number of pages	9
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	21
Issue number	10
DOIs	https://doi.org/10.1158/1055-9965.EPI-12-0526
State	Published - Oct 2012

ASJC Scopus subject areas

General Medicine

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10.1158/1055-9965.EPI-12-0526

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Warren, H., Dudbridge, F., Fletcher, O., Orr, N., Johnson, N., Hopper, J. L., Apicella, C., Southey, M. C., Mahmoodi, M., Schmidt, M. K., Broeks, A., Cornelissen, S., Braaf, L. M., Muir, K. R., Lophatananon, A., Chaiwerawattana, A., Wiangnon, S., Fasching, P. A., Beckmann, M. W., ... Dos-Santos-Silva, I. (2012). 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium. Cancer Epidemiology Biomarkers and Prevention, 21(10), 1783-1791. https://doi.org/10.1158/1055-9965.EPI-12-0526

Warren, H, Dudbridge, F, Fletcher, O, Orr, N, Johnson, N, Hopper, JL, Apicella, C, Southey, MC, Mahmoodi, M, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, LM, Muir, KR, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Sawyer, EJ, Tomlinson, I, Kerin, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guénel, P, Truong, T, Laurent-Puig, P, Mulot, C, Bojesen, SE, Nielsen, SF, Flyger, H, Nordestgaard, BG, Milne, RL, Benítez, J, Arias-Pérez, JI, Zamora, MP, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Müller, H, Arndt, V, Langheinz, A, Meindl, A, Golatta, M, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Brüning, T, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Dörk, T, Schürmann, P, Bremer, M, Hillemanns, P, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Bogdanova, N, Antonenkova, N, Rogov, Y, Bermisheva, M, Prokofyeva, D, Zinnatullina, G, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Beesley, J, Chen, X, Lambrechts, D, Smeets, A, Paridaens, R, Weltens, C, Flesch-Janys, D, Buck, K, Behrens, S, Peterlongo, P, Bernard, L, Manoukian, S, Radice, P, Couch, FJ , Vachon, C, Wang, X, Olson, J, Giles, G, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Mulligan, AM, Weerasooriya, N, Devilee, P, Tollenaar, RAEM, Martens, JWM, Seynaeve, CM, Hooning, MJ, Hollestelle, A, Jager, A, Tilanus-Linthorst, MMA, Hall, P, Czene, K, Liu, J, Li, J, Cox, A, Cross, SS, Brock, IW, Reed, MWR, Pharoah, P, Blows, FM, Dunning, AM, Ghoussaini, M, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, M, Easton, DF, Humphreys, M, Wang, Q, Peto, J & Dos-Santos-Silva, I 2012, '9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium', Cancer Epidemiology Biomarkers and Prevention, vol. 21, no. 10, pp. 1783-1791. https://doi.org/10.1158/1055-9965.EPI-12-0526

@article{22e209bbcc1a444ca5ab8f8a2d9b8f4a,

title = "9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium",

abstract = "Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype.",

author = "Helen Warren and Frank Dudbridge and Olivia Fletcher and Nick Orr and Nichola Johnson and Hopper, {John L.} and Carmel Apicella and Southey, {Melissa C.} and Maryam Mahmoodi and Schmidt, {Marjanka K.} and Annegien Broeks and Sten Cornelissen and Braaf, {Linda M.} and Muir, {Kenneth R.} and Artitaya Lophatananon and Arkom Chaiwerawattana and Surapon Wiangnon and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Ruediger Schulz-Wendtland and Sawyer, {Elinor J.} and Ian Tomlinson and Michael Kerin and Barbara Burwinkel and Frederik Marme and Andreas Schneeweiss and Christof Sohn and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Pierre Laurent-Puig and Claire Mulot and Bojesen, {Stig E.} and Nielsen, {Sune F.} and Henrik Flyger and Nordestgaard, {B{\o}rge G.} and Milne, {Roger L.} and Javier Ben{\'i}tez and Arias-P{\'e}rez, {Jos{\'e} Ignacio} and Zamora, {M. Pilar} and Hoda Anton-Culver and Argyrios Ziogas and Leslie Bernstein and Dur, {Christina Clarke} and Hermann Brenner and Heiko M{\"u}ller and Volker Arndt and Anne Langheinz and Alfons Meindl and Michael Golatta and Bartram, {Claus R.} and Schmutzler, {Rita K.} and Hiltrud Brauch and Christina Justenhoven and Thomas Br{\"u}ning and Jenny Chang-Claude and Shan Wang-Gohrke and Ursula Eilber and Thilo D{\"o}rk and Peter Sch{\"u}rmann and Michael Bremer and Peter Hillemanns and Heli Nevanlinna and Muranen, {Taru A.} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Natalia Bogdanova and Natalia Antonenkova and Yuriy Rogov and Marina Bermisheva and Darya Prokofyeva and Guzel Zinnatullina and Elza Khusnutdinova and Annika Lindblom and Sara Margolin and Arto Mannermaa and Kosma, {Veli Matti} and Hartikainen, {Jaana M.} and Vesa Kataja and Georgia Chenevix-Trench and Jonathan Beesley and Xiaoqing Chen and Diether Lambrechts and Ann Smeets and Robert Paridaens and Caroline Weltens and Dieter Flesch-Janys and Katharina Buck and Sabine Behrens and Paolo Peterlongo and Loris Bernard and Siranoush Manoukian and Paolo Radice and Couch, {Fergus J.} and Celine Vachon and Xianshu Wang and Janet Olson and Graham Giles and Laura Baglietto and McLean, {Cariona A.} and Gianluca Severi and John, {Esther M.} and Alexander Miron and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Mervi Grip and Andrulis, {Irene L.} and Knight, {Julia A.} and Mulligan, {Anna Marie} and Nayana Weerasooriya and Peter Devilee and Tollenaar, {Robert A.E.M.} and Martens, {John W.M.} and Seynaeve, {Caroline M.} and Hooning, {Maartje J.} and Antoinette Hollestelle and Agnes Jager and Tilanus-Linthorst, {Madeleine M.A.} and Per Hall and Kamila Czene and Jianjun Liu and Jingmei Li and Angela Cox and Cross, {Simon S.} and Brock, {Ian W.} and Reed, {Malcolm W.R.} and Paul Pharoah and Blows, {Fiona M.} and Dunning, {Alison M.} and Maya Ghoussaini and Alan Ashworth and Anthony Swerdlow and Michael Jones and Minouk Schoemaker and Easton, {Douglas F.} and Manjeet Humphreys and Qin Wang and Julian Peto and Isabel Dos-Santos-Silva",

year = "2012",

month = oct,

doi = "10.1158/1055-9965.EPI-12-0526",

language = "English (US)",

volume = "21",

pages = "1783--1791",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

TY - JOUR

T1 - 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer

T2 - Evidence from the Breast Cancer Association Consortium

AU - Warren, Helen

AU - Dudbridge, Frank

AU - Fletcher, Olivia

AU - Orr, Nick

AU - Johnson, Nichola

AU - Hopper, John L.

AU - Apicella, Carmel

AU - Southey, Melissa C.

AU - Mahmoodi, Maryam

AU - Schmidt, Marjanka K.

AU - Broeks, Annegien

AU - Cornelissen, Sten

AU - Braaf, Linda M.

AU - Muir, Kenneth R.

AU - Lophatananon, Artitaya

AU - Chaiwerawattana, Arkom

AU - Wiangnon, Surapon

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Schulz-Wendtland, Ruediger

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Kerin, Michael

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Schneeweiss, Andreas

AU - Sohn, Christof

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Laurent-Puig, Pierre

AU - Mulot, Claire

AU - Bojesen, Stig E.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Nordestgaard, Børge G.

AU - Milne, Roger L.

AU - Benítez, Javier

AU - Arias-Pérez, José Ignacio

AU - Zamora, M. Pilar

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Bernstein, Leslie

AU - Dur, Christina Clarke

AU - Brenner, Hermann

AU - Müller, Heiko

AU - Arndt, Volker

AU - Langheinz, Anne

AU - Meindl, Alfons

AU - Golatta, Michael

AU - Bartram, Claus R.

AU - Schmutzler, Rita K.

AU - Brauch, Hiltrud

AU - Justenhoven, Christina

AU - Brüning, Thomas

AU - Chang-Claude, Jenny

AU - Wang-Gohrke, Shan

AU - Eilber, Ursula

AU - Dörk, Thilo

AU - Schürmann, Peter

AU - Bremer, Michael

AU - Hillemanns, Peter

AU - Nevanlinna, Heli

AU - Muranen, Taru A.

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia

AU - Antonenkova, Natalia

AU - Rogov, Yuriy

AU - Bermisheva, Marina

AU - Prokofyeva, Darya

AU - Zinnatullina, Guzel

AU - Khusnutdinova, Elza

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli Matti

AU - Hartikainen, Jaana M.

AU - Kataja, Vesa

AU - Chenevix-Trench, Georgia

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Lambrechts, Diether

AU - Smeets, Ann

AU - Paridaens, Robert

AU - Weltens, Caroline

AU - Flesch-Janys, Dieter

AU - Buck, Katharina

AU - Behrens, Sabine

AU - Peterlongo, Paolo

AU - Bernard, Loris

AU - Manoukian, Siranoush

AU - Radice, Paolo

AU - Couch, Fergus J.

AU - Vachon, Celine

AU - Wang, Xianshu

AU - Olson, Janet

AU - Giles, Graham

AU - Baglietto, Laura

AU - McLean, Cariona A.

AU - Severi, Gianluca

AU - John, Esther M.

AU - Miron, Alexander

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Grip, Mervi

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Mulligan, Anna Marie

AU - Weerasooriya, Nayana

AU - Devilee, Peter

AU - Tollenaar, Robert A.E.M.

AU - Martens, John W.M.

AU - Seynaeve, Caroline M.

AU - Hooning, Maartje J.

AU - Hollestelle, Antoinette

AU - Jager, Agnes

AU - Tilanus-Linthorst, Madeleine M.A.

AU - Hall, Per

AU - Czene, Kamila

AU - Liu, Jianjun

AU - Li, Jingmei

AU - Cox, Angela

AU - Cross, Simon S.

AU - Brock, Ian W.

AU - Reed, Malcolm W.R.

AU - Pharoah, Paul

AU - Blows, Fiona M.

AU - Dunning, Alison M.

AU - Ghoussaini, Maya

AU - Ashworth, Alan

AU - Swerdlow, Anthony

AU - Jones, Michael

AU - Schoemaker, Minouk

AU - Easton, Douglas F.

AU - Humphreys, Manjeet

AU - Wang, Qin

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

PY - 2012/10

Y1 - 2012/10

N2 - Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype.

AB - Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype.

UR - http://www.scopus.com/inward/record.url?scp=84867322171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867322171&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-12-0526

DO - 10.1158/1055-9965.EPI-12-0526

M3 - Article

C2 - 22859399

AN - SCOPUS:84867322171

SN - 1055-9965

VL - 21

SP - 1783

EP - 1791

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 10

ER -

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

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