Data from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium
Authors: Warren Helen , Dudbridge Frank , Fletcher Olivia , Orr Nick , Johnson Nichola , Hopper John L. , Apicella Carmel , Southey Melissa C. , Mahmoodi Maryam , Schmidt Marjanka K. , Broeks Annegien , Cornelissen Sten , Braaf Linda M. , Muir Kenneth R. , Lophatananon Artitaya , Chaiwerawattana Arkom , Wiangnon Surapon , Fasching Peter A. , Beckmann Matthias W. , Ekici Arif B. , Schulz-Wendtland Ruediger , Sawyer Elinor J. , Tomlinson Ian , Kerin Michael , Burwinkel Barbara , Marme Frederik , Schneeweiss Andreas , Sohn Christof , Guénel Pascal , Truong Thérèse , Laurent-Puig Pierre , Mulot Claire , Bojesen Stig E , Nielsen Sune F. , Flyger Henrik , Nordestgaard Børge G , Milne Roger L. , Benítez Javier , Arias-Pérez José-Ignacio , Zamora M. Pilar , Anton-Culver Hoda , Ziogas Argyrios , Bernstein Leslie , Dur Christina Clarke , Brenner Hermann , Müller Heiko , Arndt Volker , Langheinz Anne , Meindl Alfons , Golatta Michael , Bartram Claus R. , Schmutzler Rita K. , Brauch Hiltrud , Justenhoven Christina , Brüning Thomas , Chang-Claude Jenny , Wang-Gohrke Shan , Eilber Ursula , Dörk Thilo , Schürmann Peter , Bremer Michael , Hillemanns Peter , Nevanlinna Heli , Muranen Taru A. , Aittomäki Kristiina , Blomqvist Carl , Bogdanova Natalia , Antonenkova Natalia , Rogov Yuriy , Bermisheva Marina , Prokofyeva Darya , Zinnatullina Guzel , Khusnutdinova Elza , Lindblom Annika , Margolin Sara , Mannermaa Arto , Kosma Veli-Matti , Hartikainen Jaana M. , Kataja Vesa , Chenevix-Trench Georgia , Beesley Jonathan , Chen Xiaoqing , Lambrechts Diether , Smeets Ann , Paridaens Robert , Weltens Caroline , Flesch-Janys Dieter , Buck Katharina , Behrens Sabine , Peterlongo Paolo , Bernard Loris , Manoukian Siranoush , Radice Paolo , Couch Fergus J. , Vachon Celine , Wang Xianshu , Olson Janet , Giles Graham , Baglietto Laura , McLean Cariona A. , Severi Gianluca , John Esther M. , Miron Alexander , Winqvist Robert , Pylkäs Katri , Jukkola-Vuorinen Arja , Grip Mervi , Andrulis Irene L. , Knight Julia A. , Mulligan Anna Marie , Weerasooriya Nayana , Devilee Peter , Tollenaar Robert A.E.M. , Martens John W.M. , Seynaeve Caroline M. , Hooning Maartje J. , Hollestelle Antoinette , Jager Agnes , Tilanus-Linthorst Madeleine M.A. , Hall Per , Czene Kamila , Liu Jianjun , Li Jingmei , Cox Angela , Cross Simon S. , Brock Ian W. , Reed Malcolm W.R. , Pharoah Paul , Blows Fiona M. , Dunning Alison M. , Ghoussaini Maya , Ashworth Alan , Swerdlow Anthony , Jones Michael , Schoemaker Minouk , Easton Douglas F. , Humphreys Manjeet , Wang Qin , Peto Julian , dos-Santos-Silva Isabel 
Published: March 2023

<div>Abstract<p><b>Background:</b> Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).</p><p><b>Methods:</b> 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).</p><p><b>Results:</b> 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, <i>P</i> = 2.01 × 10<sup>−29</sup>] 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; <i>P</i> for heterogeneity (<i>P</i><sub>het</sub>) = 1.3 × 10<sup>−143</sup>], but no evidence of ethnic differences in per allele OR (<i>P</i><sub>het</sub> = 0.43). rs865686 was associated with estrogen receptor–positive (ER<sup>+</sup>) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; <i>P</i> = 3.13 × 10<sup>−22</sup>) but less strongly, if at all, with ER-negative (ER<sup>−</sup>) disease (OR, 0.98; 95% CI, 0.94–1.02; <i>P</i> = 0.26; <i>P</i><sub>het</sub> = 1.16 × 10<sup>−6</sup>), 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 the G allele with increasing age at diagnosis (<i>P</i> for linear trend = 0.0095), but only among women with ER<sup>+</sup> tumors.</p><p><b>Conclusions:</b> This study is the first to show that rs865686 is a susceptibility marker for ER<sup>+</sup> breast cancer.</p><p><b>Impact:</b> The findings further support the view that genetic susceptibility varies according to tumor subtype. <i>Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR</i>.</p></div>