A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

Afshan Siddiq, Fergus J Couch, Gary K. Chen, Sara Lindström, Diana M Eccles, Robert C. Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, Christine B. Ambrosone, Kristiina Aittomäki, Pilar Amiano, Carmel Apicella, Laura Baglietto, Elisa V. Bandera, Matthias W. Beckmann, Christine D Berg, Leslie Bernstein, Carl BlomqvistHiltrud Brauch, Louise Brinton, Quang Minh Bui, Julie E Buring, Saundra S. Buys, Daniele Campa, Jane E. Carpenter, Daniel I Chasman, Jenny Chang-Claude, Constance Chen, Françoise Clavel-Chapelon, Angela Cox, Simon S Cross, Kamila Czene, Sandra L. Deming Halverson, Robert B. Diasio, W. Ryan Diver, Alison M Dunning, Lorraine Durcan, Arif B Ekici, Peter A. Fasching, Heather Spencer Feigelson, Laura Fejerman, Jonine D Figueroa, Olivia Fletcher, Dieter Flesch-Janys, Mia M Gaudet, Susan M. Gerty, Jorge L. Rodriguez-Gil, Graham G. Giles, Carla H Van Gils, Andrew K. Godwin, Nikki J. Graham, Dario Greco, Per Hall, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Robert N Hoover, John L. Hopper, Jennifer J. Hu, Scott Huntsman, Sue A. Ingles, Astrid K Irwanto, Claudine Janet Diana Isaacs, Kevin B. Jacobs, Esther M. John, Christina Justenhoven, Rudolf J Kaaks, Laurence N Kolonel, Gerhard A. Coetzee, Mark G Lathrop, Loic Le Marchand, Adam M. Lee, I-Min Lee, Timothy Lesnick, Peter Lichtner, Jianjun Liu, Eiliv Eylin Lund, Enes Makalic, Nicholas Gordon Martin, Catriona A. McLean, Hanne Meijers-Heijboer, Alfons Meindl, Penelope Miron, Kristine R. Monroe, Grant W Montgomery, Bertram Müller-Myhsok, Stefan Nickels, Sarah J. Nyante, Curtis Olswold, Kim Overvad, Domenico Palli, Daniel J. Park, Julie R. Palmer, Harsh Pathak, Julian Peto, Paul D P Pharoah, Nazneen Rahman, Fernando Rivadeneira, Daniel F. Schmidt, Rita K. Schmutzler, Susan Slager, Melissa C. Southey, Kristen N. Stevens, Hans Peter Sinn, Michael F. Press, Eric Ross, Elio B Riboli, Paul M Ridker, Fredrick R. Schumacher, Gianluca Severi, Isabel dos Santos Silva, Jennifer L Stone, Malin Sund, William J Tapper, Michael J Thun, Ruth C Travis, Clare Turnbull, Andre G Uitterlinden, Quinten Waisfisz, Xianshu Wang, Zhaoming Wang, Jo Ellen Weaver, Rüdiger Schulz-Wendtland, Lynne R. Wilkens, David Berg, Wei Zheng, Regina G Ziegler, Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J. Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon, Australian Breast Cancer Tissue Bank Investigators

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Abstract

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10-8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10-6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10-9), and with both ER-positive (OR = 1.09; P = 1.5 × 10-5) and ER-negative (OR = 1.16, P = 2.5 × 10-7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Original languageEnglish
Article numberdds381
Pages (from-to)5373-5384
Number of pages12
JournalHuman Molecular Genetics
Volume21
Issue number24
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Siddiq, A., Couch, F. J., Chen, G. K., Lindström, S., Eccles, D. M., Millikan, R. C., Michailidou, K., Stram, D. O., Beckmann, L., Rhie, S. K., Ambrosone, C. B., Aittomäki, K., Amiano, P., Apicella, C., Baglietto, L., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., ... Australian Breast Cancer Tissue Bank Investigators (2012). A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Human Molecular Genetics, 21(24), 5373-5384. [dds381]. https://doi.org/10.1093/hmg/dds381