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9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium
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; Ekici, A B; Schulz-Wendtland, R; Sawyer, E J; Tomlinson, I; Kerin, M; Burwinkel, B; Marme, F; Schneeweiss, A; Sohn, C; Guenel, P; Truong, T; Laurent-Puig, P; Mulot, C; Bojesen, S E; Nielsen, S F; Flyger, H; Nordestgaard, B G; Milne, R L; Benitez, J; Arias-Perez, J I; Zamora, M P; Anton-Culver, H; Ziogas, A; Bernstein, L; Dur, C C; Brenner, H; Muller, H; Arndt, V; Langheinz, A; Meindl, A; Golatta, M; Bartram, C R; Schmutzler, R K; Brauch, H; Justenhoven, C; Bruning, T; Chang-Claude, J; Wang-Gohrke, S; Eilber, U; Dork, T; Schurmann, P; Bremer, M; Hillemanns, P; Nevanlinna, H; Muranen, T A; Aittomaki, K; Blomqvist, C; Bogdanova, N; Antonenkova, N; Rogov, Y; Bermisheva, M; Prokofyeva, D; Zinnatullina, G; Khusnutdinova, E; Lindblom, A; Margolin, S; Mannermaa, A; Kosma, V M; Hartikainen, J M; 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, F J; Vachon, C; Wang, X; Olson, J; Giles, G; Baglietto, L; McLean, C A; Severi, G; John, E M; Miron, A; Winqvist, R; Pylkas, K; Jukkola-Vuorinen, A; Grip, M; Andrulis, I L; Knight, J A; Mulligan, A M; Weerasooriya, N; Devilee, P; Tollenaar, R A; Martens, J W; Seynaeve, C M; Hooning, M J; Hollestelle, A; Jager, A; Tilanus-Linthorst, M M; Hall, P; Czene, K; Liu, J; Li, J; Cox, A; Cross, S S; Brock, I W; Reed, M W; Pharoah, P; Blows, F M; Dunning, A M; Ghoussaini, M; Ashworth, A; Swerdlow, A; Jones, M; Schoemaker, M; Easton, D F; Humphreys, M; Wang, Q; Peto, J; Dos-Santos-Silva, I
Cancer Epidemiol Biomarkers Prev. 2012;21(10):1783-1791.
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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.
Bibliographic metadata
- 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
- Ekici, A B
- Schulz-Wendtland, R
- Sawyer, E J
- Tomlinson, I
- Kerin, M
- Burwinkel, B
- Marme, F
- Schneeweiss, A
- Sohn, C
- Guenel, P
- Truong, T
- Laurent-Puig, P
- Mulot, C
- Bojesen, S E
- Nielsen, S F
- Flyger, H
- Nordestgaard, B G
- Milne, R L
- Benitez, J
- Arias-Perez, J I
- Zamora, M P
- Anton-Culver, H
- Ziogas, A
- Bernstein, L
- Dur, C C
- Brenner, H
- Muller, H
- Arndt, V
- Langheinz, A
- Meindl, A
- Golatta, M
- Bartram, C R
- Schmutzler, R K
- Brauch, H
- Justenhoven, C
- Bruning, T
- Chang-Claude, J
- Wang-Gohrke, S
- Eilber, U
- Dork, T
- Schurmann, P
- Bremer, M
- Hillemanns, P
- Nevanlinna, H
- Muranen, T A
- Aittomaki, K
- Blomqvist, C
- Bogdanova, N
- Antonenkova, N
- Rogov, Y
- Bermisheva, M
- Prokofyeva, D
- Zinnatullina, G
- Khusnutdinova, E
- Lindblom, A
- Margolin, S
- Mannermaa, A
- Kosma, V M
- Hartikainen, J M
- 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, F J
- Vachon, C
- Wang, X
- Olson, J
- Giles, G
- Baglietto, L
- McLean, C A
- Severi, G
- John, E M
- Miron, A
- Winqvist, R
- Pylkas, K
- Jukkola-Vuorinen, A
- Grip, M
- Andrulis, I L
- Knight, J A
- Mulligan, A M
- Weerasooriya, N
- Devilee, P
- Tollenaar, R A
- Martens, J W
- Seynaeve, C M
- Hooning, M J
- Hollestelle, A
- Jager, A
- Tilanus-Linthorst, M M
- Hall, P
- Czene, K
- Liu, J
- Li, J
- Cox, A
- Cross, S S
- Brock, I W
- Reed, M W
- Pharoah, P
- Blows, F M
- Dunning, A M
- Ghoussaini, M
- Ashworth, A
- Swerdlow, A
- Jones, M
- Schoemaker, M
- Easton, D F
- Humphreys, M
- Wang, Q
- Peto, J
- Dos-Santos-Silva, I
- 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 Guenel, Pascal Truong, Therese Laurent-Puig, Pierre Mulot, Claire Bojesen, Stig E Nielsen, Sune F Flyger, Henrik Nordestgaard, Borge G Milne, Roger L Benitez, Javier Arias-Perez, Jose-Ignacio Zamora, M Pilar Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Dur, Christina Clarke Brenner, Hermann Muller, Heiko Arndt, Volker Langheinz, Anne Meindl, Alfons Golatta, Michael Bartram, Claus R Schmutzler, Rita K Brauch, Hiltrud Justenhoven, Christina Bruning, Thomas for The GENICA Network Chang-Claude, Jenny Wang-Gohrke, Shan Eilber, Ursula Dork, Thilo Schurmann, Peter Bremer, Michael Hillemanns, Peter Nevanlinna, Heli Muranen, Taru A Aittomaki, 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 for kConFab Investigators Australian Ovarian Cancer Study Group 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 Pylkas, 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 Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Cancer Epidemiol Biomarkers Prev. 2012 Oct;21(10):1783-1791. Epub 2012 Aug 2.