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- DOI: 10.1093/hmg/ddu311
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Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium
Milne, R L; Burwinkel, B; Michailidou, K; Arias-Perez, J I; Zamora, M P; Menendez-Rodriguez, P; Hardisson, D; Mendiola, M; Gonzalez-Neira, A; Pita, G; Alonso, M R; Dennis, J; Wang, Q; Bolla, M K; Swerdlow, A; Ashworth, A; Orr, N; Schoemaker, M; Ko, Y D; Brauch, H; Hamann, U; Andrulis, I L; Knight, J A; Glendon, G; Tchatchou, S; Investigators, K; Matsuo, K; Ito, H; Iwata, H; Tajima, K; Li, J; Brand, J S; Brenner, H; Dieffenbach, A K; Arndt, V; Stegmaier, C; Lambrechts, D; Peuteman, G; Christiaens, M R; Smeets, A; Jakubowska, A; Lubinski, J; Jaworska-Bieniek, K; Durda, K; Hartman, M; Hui, M; Lim, W Y; Chan, C W; Marme, F; Yang, R; Bugert, P; Lindblom, A; Margolin, S; Garcia-Closas, M; Chanock, S J; Lissowska, J; Figueroa, J D; Bojesen, S E; Nordestgaard, B G; Flyger, H; Hooning, M J; Kriege, M; van den Ouweland, A M; Koppert, L B; Fletcher, O; Johnson, N; Dos-Santos-Silva, I; Peto, J; Zheng, W; Deming-Halverson, S; Shrubsole, M J; Long, J; Chang-Claude, J; Rudolph, A; Seibold, P; Flesch-Janys, D; Winqvist, R; Pylkas, K; Jukkola-Vuorinen, A; Grip, M; Cox, A; Cross, S S; Reed, M W; Schmidt, M K; Broeks, A; Cornelissen, S; Braaf, L; Kang, D; Choi, J Y; Park, S K; Noh, D Y; Simard, J; Dumont, M; Goldberg, M S; Labreche, F; Fasching, P A; Hein, A; Ekici, A B; Beckmann, M W; Radice, P; Peterlongo, P; Azzollini, J; Barile, M; Sawyer, E; Tomlinson, I; Kerin, M; Miller, N; Hopper, J L; Schmidt, D F; Makalic, E; Southey, M C; Teo, S H; Yip, C H; Sivanandan, K; Tay, W T; Shen, C Y; Hsiung, C N; Yu, J C; Hou, M F; Guenel, P; Truong, T; Sanchez, M; Mulot, C; Blot, W; Cai, Q; Nevanlinna, H; Muranen, T A; Aittomaki, K; Blomqvist, C; Wu, A H; Tseng, C C; Van Den Berg, D; Stram, D O; Bogdanova, N; Dork, T; Muir, K; Lophatananon, A; Stewart-Brown, S; Siriwanarangsan, P; Mannermaa, A; Kataja, V; Kosma, V M; Hartikainen, J M; Shu, X O; Lu, W; Gao, Y T; Zhang, B; Couch, F J; Toland, A E; Yannoukakos, D; Sangrajrang, S; McKay, J; Wang, X; Olson, J E; Vachon, C; Purrington, K; Severi, G; Baglietto, L; Haiman, C A; Henderson, B E; Schumacher, F; Le Marchand, L; Devilee, P; Tollenaar, R A; Seynaeve, C; Czene, K; Eriksson, M; Humphreys, K; Darabi, H; Ahmed, S; Shah, M; Pharoah, P D; Hall, P; Giles, G G; Benitez, J; Dunning, A M; Chenevix-Trench, G; Easton, D F
Hum Mol Genet. 2014;.
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Full-text held externally
- DOI: 10.1093/hmg/ddu311
Abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46,450 cases and 42,600 controls) and analysed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 (rs1053338, per-allele OR=1.07, 95%CI=1.04-1.10, P=2.9x10-6), AKAP9-M463I at 7q21 (rs6964587, OR=1.05, 95%CI=1.03-1.07, P=1.7x10-6) and NEK10-L513S at 3p24 (rs10510592, OR=1.10, 95%CI=1.07-1.12, P=5.1x10-17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine GWAS: for ATXN7-K264R, OR=1.07 (95%CI=1.05-1.10, P=1.0x10-8); for AKAP9-M463I, OR=1.05 (95%CI=1.04-1.07, P=2.0x10-10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known genome-wide association study (GWAS) hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Bibliographic metadata
- Milne, R L
- Burwinkel, B
- Michailidou, K
- Arias-Perez, J I
- Zamora, M P
- Menendez-Rodriguez, P
- Hardisson, D
- Mendiola, M
- Gonzalez-Neira, A
- Pita, G
- Alonso, M R
- Dennis, J
- Wang, Q
- Bolla, M K
- Swerdlow, A
- Ashworth, A
- Orr, N
- Schoemaker, M
- Ko, Y D
- Brauch, H
- Hamann, U
- Andrulis, I L
- Knight, J A
- Glendon, G
- Tchatchou, S
- Investigators, K
- Matsuo, K
- Ito, H
- Iwata, H
- Tajima, K
- Li, J
- Brand, J S
- Brenner, H
- Dieffenbach, A K
- Arndt, V
- Stegmaier, C
- Lambrechts, D
- Peuteman, G
- Christiaens, M R
- Smeets, A
- Jakubowska, A
- Lubinski, J
- Jaworska-Bieniek, K
- Durda, K
- Hartman, M
- Hui, M
- Lim, W Y
- Chan, C W
- Marme, F
- Yang, R
- Bugert, P
- Lindblom, A
- Margolin, S
- Garcia-Closas, M
- Chanock, S J
- Lissowska, J
- Figueroa, J D
- Bojesen, S E
- Nordestgaard, B G
- Flyger, H
- Hooning, M J
- Kriege, M
- van den Ouweland, A M
- Koppert, L B
- Fletcher, O
- Johnson, N
- Dos-Santos-Silva, I
- Peto, J
- Zheng, W
- Deming-Halverson, S
- Shrubsole, M J
- Long, J
- Chang-Claude, J
- Rudolph, A
- Seibold, P
- Flesch-Janys, D
- Winqvist, R
- Pylkas, K
- Jukkola-Vuorinen, A
- Grip, M
- Cox, A
- Cross, S S
- Reed, M W
- Schmidt, M K
- Broeks, A
- Cornelissen, S
- Braaf, L
- Kang, D
- Choi, J Y
- Park, S K
- Noh, D Y
- Simard, J
- Dumont, M
- Goldberg, M S
- Labreche, F
- Fasching, P A
- Hein, A
- Ekici, A B
- Beckmann, M W
- Radice, P
- Peterlongo, P
- Azzollini, J
- Barile, M
- Sawyer, E
- Tomlinson, I
- Kerin, M
- Miller, N
- Hopper, J L
- Schmidt, D F
- Makalic, E
- Southey, M C
- Teo, S H
- Yip, C H
- Sivanandan, K
- Tay, W T
- Shen, C Y
- Hsiung, C N
- Yu, J C
- Hou, M F
- Guenel, P
- Truong, T
- Sanchez, M
- Mulot, C
- Blot, W
- Cai, Q
- Nevanlinna, H
- Muranen, T A
- Aittomaki, K
- Blomqvist, C
- Wu, A H
- Tseng, C C
- Van Den Berg, D
- Stram, D O
- Bogdanova, N
- Dork, T
- Muir, K
- Lophatananon, A
- Stewart-Brown, S
- Siriwanarangsan, P
- Mannermaa, A
- Kataja, V
- Kosma, V M
- Hartikainen, J M
- Shu, X O
- Lu, W
- Gao, Y T
- Zhang, B
- Couch, F J
- Toland, A E
- Yannoukakos, D
- Sangrajrang, S
- McKay, J
- Wang, X
- Olson, J E
- Vachon, C
- Purrington, K
- Severi, G
- Baglietto, L
- Haiman, C A
- Henderson, B E
- Schumacher, F
- Le Marchand, L
- Devilee, P
- Tollenaar, R A
- Seynaeve, C
- Czene, K
- Eriksson, M
- Humphreys, K
- Darabi, H
- Ahmed, S
- Shah, M
- Pharoah, P D
- Hall, P
- Giles, G G
- Benitez, J
- Dunning, A M
- Chenevix-Trench, G
- Easton, D F
- Milne, Roger L Burwinkel, Barbara Michailidou, Kyriaki Arias-Perez, Jose-Ignacio Zamora, M Pilar Menendez-Rodriguez, Primitiva Hardisson, David Mendiola, Marta Gonzalez-Neira, Anna Pita, Guillermo Alonso, M Rosario Dennis, Joe Wang, Qin Bolla, Manjeet K Swerdlow, Anthony Ashworth, Alan Orr, Nick Schoemaker, Minouk Ko, Yon-Dschun Brauch, Hiltrud Hamann, Ute The GENICA Network Andrulis, Irene L Knight, Julia A Glendon, Gord Tchatchou, Sandrine Investigators, kConFab Australian Ovarian Cancer Study Group Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Li, Jingmei Brand, Judith S Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Lambrechts, Diether Peuteman, Gilian Christiaens, Marie-Rose Smeets, Ann Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katazyna Hartman, Mikael Hui, Miao Lim, Wei Yen Chan, Ching Wan Marme, Federick Yang, Rongxi Bugert, Peter Lindblom, Annika Margolin, Sara Garcia-Closas, Montserrat Chanock, Stephen J Lissowska, Jolanta Figueroa, Jonine D Bojesen, Stig E Nordestgaard, Borge G Flyger, Henrik Hooning, Maartje J Kriege, Mieke van den Ouweland, Ans M W Koppert, Linetta B Fletcher, Olivia Johnson, Nichola Dos-Santos-Silva, Isabel Peto, Julian Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha J Long, Jirong Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Cox, Angela Cross, Simon S Reed, Malcolm W R Schmidt, Marjanka K Broeks, Annegien Cornelissen, Sten Braaf, Linde Kang, Daehee Choi, Ji-Yeob Park, Sue K Noh, Dong-Young Simard, Jacques Dumont, Martine Goldberg, Mark S Labreche, France Fasching, Peter A Hein, Alexander Ekici, Arif B Beckmann, Matthias W Radice, Paolo Peterlongo, Paolo Azzollini, Jacopo Barile, Monica Sawyer, Elinor Tomlinson, Ian Kerin, Michael Miller, Nicola Hopper, John L Schmidt, Daniel F Makalic, Enes Southey, Melissa C Teo, Soo Hwang Yip, Cheng Har Sivanandan, Kavitta Tay, Wan-Ting Shen, Chen-Yang Hsiung, Chia-Ni Yu, Jyh-Cherng Hou, Ming-Feng Guenel, Pascal Truong, Therese Sanchez, Marie Mulot, Claire Blot, William Cai, Qiuyin Nevanlinna, Heli Muranen, Taru A Aittomaki, Kristiina Blomqvist, Carl Wu, Anna H Tseng, Chiu-Chen Van Den Berg, David Stram, Daniel O Bogdanova, Natalia Dork, Thilo Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Zhang, Ben Couch, Fergus J Toland, Amanda E Tnbcc Yannoukakos, Drakoulis Sangrajrang, Suleeporn McKay, James Wang, Xianshu Olson, Janet E Vachon, Celine Purrington, Kristen Severi, Gianluca Baglietto, Laura Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Devilee, Peter Tollenaar, Robert A E M Seynaeve, Caroline Czene, Kamila Eriksson, Mikael Humphreys, Keith Darabi, Hatef Ahmed, Shahana Shah, Mitul Pharoah, Paul D P Hall, Per Giles, Graham G Benitez, Javier Dunning, Alison M Chenevix-Trench, Georgia Easton, Douglas F Human molecular genetics Hum Mol Genet. 2014 Jun 18. pii: ddu311.