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. 2012 Oct;21(10):1783-91.
doi: 10.1158/1055-9965.EPI-12-0526. Epub 2012 Aug 2.

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

Helen Warren  1 , 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; GENICA Network; 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; kConFab Investigators; Australian Ovarian Cancer Study Group; 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
Affiliations

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

Helen Warren et al. Cancer Epidemiol Biomarkers Prev. 2012 Oct.

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 (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 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; P(het) = 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 the G allele 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.

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Figures

Figure 1
Figure 1
Forest plot of the association of 9q31.2-rs865686 with breast cancer risk among women of European ancestry in the original GWAS, all stages combined (11), and replication within the Breast Cancer Association Consortium (BCAC). Ca, no. cases; Co, no. controls; MAF, minor allele frequency. Study abbreviations as in Supplementary Table S1. * The discovery set (see Results) comprises data from 2 BCAC studies that had contributed data to the GWAS analysis [BBCS contributed data on 1,711 (out of the 1,978 subjects examined here) to stages 1 and 2 of the GWAS; UKBGS contributed data on 4,621 (out of the 4,661 subjects examined here) to stage 3 of the GWAS].
Figure 2
Figure 2
9q31.2-rs865686 and breast cancer risk amongst women of European ancestry stratifying by ER, PR, and HER2 receptor status*. Ca, no. cases; Co, no. controls; * P for heterogeneity (Phet) in the OR by ER status: 6.9 × 10–4 amongst PR– tumors and 0.52 amongst PR+ tumors. Phet in the OR by PR status: 0.13 amongst ER– cases and 0.52 amongst ER+ cases.
See this image and copyright information in PMC

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