Candidate variant association studies havebeenlargely unsuccessful in identifyingcommonbreast 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 werecombined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04-1.10, P 5 2.9 3 1026], AKAP9-M463I at 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03-1.07, P 5 1.7 3 1026) and NEK10-L513S at 3p24 (rs10510592, OR 5 1.10, 95% CI 5 1.07-1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical significance in acombined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05-1.10, P 5 1.0 3 1028); for AKAP9-M463I, OR 5 1.05 (95% CI 5 1.04-1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two regions suggested that intronic SNPsnearby are more strongly associated with disease risk.Wehave 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 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.

Common non-synonymous SNPs associated with breast cancer susceptibility: Findings from the Breast Cancer Association Consortium

BAGLIETTO, LAURA;
2014

Abstract

Candidate variant association studies havebeenlargely unsuccessful in identifyingcommonbreast 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 werecombined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04-1.10, P 5 2.9 3 1026], AKAP9-M463I at 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03-1.07, P 5 1.7 3 1026) and NEK10-L513S at 3p24 (rs10510592, OR 5 1.10, 95% CI 5 1.07-1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical significance in acombined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05-1.10, P 5 1.0 3 1028); for AKAP9-M463I, OR 5 1.05 (95% CI 5 1.04-1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two regions suggested that intronic SNPsnearby are more strongly associated with disease risk.Wehave 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 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.
Milne, Roger L.; Burwinkel, Barbara; Michailidou, Kyriaki; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez Rodríguez, Primitiva; Hardisson, David; Mendiola, Marta; González Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Dennis, Joe; Wang, Qin; Bolla, Manjeet K.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk; Ko, Yon Dschun; Brauch, Hiltrud; Hamann, Ute; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; 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; García Closas, Montserrat; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Bojesen, Stig E.; Nordestgaard, Børge 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; Pylkäs, 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, Jiyeob; Park, Sue K.; Noh, Dong Young; Simard, Jacques; Dumont, Martine; Goldberg, Mark S.; Labrèche, 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; Guénel, Pascal; Truong, Therese; Sanchez, Marie; Mulot, Claire; Blot, William; Cai, Qiuyin; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Wu, Anna H.; Tseng, Chiu Chen; Van Den Berg, David; Stram, Daniel O.; Bogdanova, Natalia; Thilo Dörk, Null; 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.; 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; Marchand, Loic Le; 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.; Benítez, Javier; Dunning, Alison M.; Chenevix Trench, Georgia; Easton, Douglas F.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/817948
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