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; +133 more... 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 AEM Tollenaar; John WM Martens; Caroline M Seynaeve; Maartje J Hooning; Antoinette Hollestelle; Agnes Jager; Madeleine MA Tilanus-Linthorst; Per Hall; Kamila Czene; Jianjun Liu; Jingmei Li; Angela Cox; Simon S Cross; Ian W Brock; Malcolm WR 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

; (2012) 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium. Cancer epidemiology, biomarkers & prevention, 21 (10). pp. 1783-1791. ISSN 1055-9965 DOI: 10.1158/1055-9965.EPI-12-0526

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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.