9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

H Warren, F Dudbridge, O Fletcher, N Orr, N Johnson, J L Hopper, C Apicella, M C Southey, M Mahmoodi, M K Schmidt, A Broeks, S Cornelissen, L M Braaf, K R Muir, A Lophatananon, A Chaiwerawattana, S Wiangnon, P A Fasching, M W Beckmann, A B EkiciR Schulz-Wendtland, E J Sawyer, I Tomlinson, M Kerin, B Burwinkel, F Marme, A Schneeweiss, C Sohn, P Guenel, T Truong, P Laurent-Puig, C Mulot, S E Bojesen, S F Nielsen, H Flyger, B G Nordestgaard, R L Milne, J Benitez, J I Arias-Perez, M P Zamora, H Anton-Culver, A Ziogas, L Bernstein, C C Dur, H Brenner, H Muller, V Arndt, A Langheinz, A Meindl, M Golatta, C R Bartram, R K Schmutzler, H Brauch, C Justenhoven, T Bruning, J Chang-Claude, S Wang-Gohrke, U Eilber, T Dork, P Schurmann, M Bremer, P Hillemanns, H Nevanlinna, T A Muranen, K Aittomaki, C Blomqvist, N Bogdanova, N Antonenkova, Y Rogov, M Bermisheva, D Prokofyeva, G Zinnatullina, E Khusnutdinova, A Lindblom, S Margolin, A Mannermaa, V M Kosma, J M Hartikainen, V Kataja, G Chenevix-Trench, J Beesley, X Chen, D Lambrechts, A Smeets, R Paridaens, C Weltens, D Flesch-Janys, K Buck, S Behrens, P Peterlongo, L Bernard, S Manoukian, P Radice, F J Couch, C Vachon, X Wang, J Olson, G Giles, L Baglietto, C A McLean, G Severi, E M John, A Miron, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, I L Andrulis, J A Knight, A M Mulligan, N Weerasooriya, P Devilee, R A Tollenaar, J W Martens, C M Seynaeve, M J Hooning, A Hollestelle, A Jager, M M Tilanus-Linthorst, P Hall, K Czene, J Liu, J Li, A Cox, S S Cross, I W Brock, M W Reed, P Pharoah, F M Blows, A M Dunning, M Ghoussaini, A Ashworth, A Swerdlow, M Jones, M Schoemaker, D F Easton, M Humphreys, Q Wang, J Peto, I Dos-Santos-Silva

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    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 x 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 x 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 x 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 x 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. Cancer Epidemiol Biomarkers Prev; 21(10); 1783-. (c)2012 AACR.
    Original languageEnglish
    Pages (from-to)1783-1791
    Number of pages9
    JournalCancer Epidemiology, Biomarkers & Prevention
    Volume21
    Issue number10
    DOIs
    Publication statusPublished - 2012

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