Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Lin, W-Y, Camp, N J, Ghoussaini, M, Beesley, J, Michailidou, K, Hopper, J L, Apicella, C, Southey, M C, Stone, J, Schmidt, M K, Broeks, A, Van't Veer, L J, Th Rutgers, E J, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, P A, Haeberle, L, Ekici, A B, Beckmann, M W, Peto, J, Dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, M K, Wang, Q, Dennis, J, Sawyer, E J, Cheng, T, Tomlinson, I, Kerin, M J, Miller, N, Marmé, F, Surowy, H M, Burwinkel, B, Guénel, P, Truong, T, Menegaux, F, Mulot, C, Bojesen, S E, Nordestgaard, B G, Nielsen, S F, Flyger, H, Benitez, J, Pilar Zamora, M, Perez, J I A, Menéndez, P, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Anton-Culver, H, Brenner, H, Dieffenbach, A K, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, R K, Müller-Myhsok, B, Brauch, H, Brűning, T, Ko, Y-D, Tessier, D C, Vincent, D, Bacot, F, Nevanlinna, H, Aittomäki, K, Blomqvist, C, Khan, S, Matsuo, K, Ito, H, Iwata, H, Horio, A, Bogdanova, N V, Antonenkova, N N, Dörk, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J M, Wu, A H, Tseng, C-C, Van Den Berg, D, Stram, D O, Neven, P, Wauters, E, Wildiers, H, Lambrechts, D, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Bonanni, B, Couch, F J, Wang, X, Vachon, C, Purrington, K, Giles, G G, Milne, R L, Mclean, C, Haiman, C A, Henderson, B E, Schumacher, F, Marchand, L L, Simard, J, Goldberg, M S, Labrèche, F, Dumont, M, Teo, S H, Yip, C H, Hassan, N, Vithana, E N, Kristensen, V, Zheng, W, Deming-Halverson, S, Shrubsole, M J, Long, J, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, I L, Knight, J A, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, R A E M, Seynaeve, C, Van Asperen, C J, García-Closas, M, Figueroa, J, Lissowska, J, Brinton, L, Czene, K, Darabi, H, Eriksson, M, Brand, J S, Hooning, M J, Hollestelle, A, Van DenOuweland, A M W, Jager, A, Li, J, Liu, J, Humphreys, K, Shu, X-O, Lu, W, Gao, Y T, Cai, H, Cross, S S, Reed, M, Blot, W, Signorello, L B, Cai, Q, Pharoah, P D P, Perkins, B, Shah, M, Blows, F M, Kang, D, Yoo, K-Y, Noh, D-Y, Hartman, M, Miao, H, Chia, K S, Putti, T C, Hamann, U, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, C S, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, A E, Yannoukakos, D, Shen, C-Y, Hsiung, C-N, Wu, P-E, Ding, S-L, Ashworth, A, Jones, M, Orr, N, Swerdlow, A J, Tsimiklis, H, Makalic, E, Schmidt, D F, Bui, Q M, Chanock, S J, Hunter, D J, Hein, R, Dahmen, N, Beckmann, L, Aaltonen, K, Muranen, T A, Heikkinen, T, Irwanto, A, Rahman, N, Turnbull, C A, Waisfisz, Q, Meijers-Heijboer, H E J, Adank, M A, Van Der Luijt, R B, Hall, P, Chenevix-Trench, G, Dunning, A, Easton, D F and Cox, A (2015) Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. Human Molecular Genetics, 24 (1). pp. 285-298. ISSN 0964-6906

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Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95 confidence interval OR (95% confidence interval, CI) for the minor allele of 1.05 (1.03-1.07), P = 1 × 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P=3 × 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8might be the target gene, suggesting amechanism involving apoptosis. © The Author 2014.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Division of Medical Education
Depositing User: Esme Acton-Stewart
Date Deposited: 18 Mar 2016 12:53
Last Modified: 18 Mar 2016 12:53
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