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

WY Lin; NJ Camp; M Ghoussaini; J Beesley; K Michailidou; JL Hopper; C Apicella; MC Southey; J Stone; MK (Marjanka) Schmidt; A Broeks; LJ (Laura) van 't Veer; EJT Rutgers; K Muir; A Lophatananon; S Stewart-Brown; P Siriwanarangsan; PA Fasching; L Haeberle; AB Ekici; MW Beckmann; J Peto; I dos-Santos-Silva; O Fletcher; N Johnson; MK Bolla; Q (Qing) Wang; J Dennis; EJ Sawyer; T Cheng; I Tomlinson; MJ Kerin; N Miller; F Marme; HM Surowy; B Burwinkel; P Guenel; T Truong; F Menegaux; C Mulot; SE Bojesen; BG Nordestgaard; SF Nielsen; H Flyger; J Benitez; MP Zamora; JIA Perez; P Menendez; A Gonzalez-Neira; G Pita; MR Alonso; N Alvarez; D Herrera; H Anton-Culver; H Brenner; AK Dieffenbach; V Arndt; C Stegmaier; A Meindl; P Lichtner; RK Schmutzler; B Muller-Myhsok; H Brauch; T Bruning; YD Ko; DC Tessier; D Vincent; F Bacot; H Nevanlinna; K Aittomaki; C Blomqvist; Salima Khan; K Matsuo; H Ito; H Iwata; A Horio; NV Bogdanova; NN Antonenkova; T Dork; A Lindblom; S Margolin; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; AH Wu; CC Tseng; D van den Berg; DO Stram; P Neven; Erwin Wauters; H Wildiers; D Lambrechts; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; P Radice; P Peterlongo; S Manoukian; B Bonanni; FJ Couch; XS Wang; C Vachon; K Purrington; GG Giles; RL Milne; C McLean; CA Haiman; BE Henderson; F Schumacher; L Le Marchand; J Simard; MS Goldberg; F Labreche; M Dumont; SH Teo; CH Yip; N Hassan; EN Vithana; V Kristensen; W Zheng; S Deming-Halverson; MJ Shrubsole; JR Long; R Winqvist; K Pylkas; A Jukkola-Vuorinen; S Kauppila; IL Andrulis; JA Knight; G Glendon; S Tchatchou; P Devilee; RAEM Tollenaar; Caroline Seynaeve; CJ van Asperen; M Garcia-Closas; J Figueroa; J Lissowska; L Brinton; K Czene; H Darabi; M Eriksson; JS Brand; Maartje Hooning; Antoinette Hollestelle; Ans van den Ouweland; Agnes Jager; JM Li; JJ Liu; K Humphreys; XO Shu; W Lu; YT Gao; H Cai; SS Cross; MWR Reed; W Blot; LB Signorello; QY Cai; PDP Pharoah; B Perkins; M Shah; FM Blows; D Kang; KY Yoo; DY Noh; M Hartman; H Miao; KS Chia; TC Putti; U Hamann; C Luccarini; C Baynes; S (Shahana) Ahmed; M Maranian; CS Healey; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; S Sangrajrang; V Gaborieau; P Brennan; J Mckay; S Slager; AE Toland; D Yannoukakos; CY Shen; CN Hsiung; PE Wu; SL Ding; A Ashworth; M Jones; N Orr; AJ Swerdlow; H Tsimiklis; E Makalic; DF Schmidt; QM Bui; SJ Chanock; DJ Hunter; R Hein; N Dahmen; L Beckmann; K Aaltonen; TA Muranen; T Heikkinen; A Irwanto; N Rahman; CA Turnbull; Q Waisfisz; HEJ Meijers-Heijboer; MA (Muriel) Adank; RB van der Luijt; P Hall; G Chenevix-Trench; A Dunning; DF Easton; A Cox

doi:10.1093/hmg/ddu431

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

WY Lin, NJ Camp, M Ghoussaini, J Beesley, K Michailidou, JL Hopper, C Apicella, MC Southey, J Stone, MK (Marjanka) Schmidt, A Broeks, LJ (Laura) van 't Veer, EJT Rutgers, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, PA Fasching, L Haeberle, AB EkiciMW Beckmann, J Peto, I dos-Santos-Silva, O Fletcher, N Johnson, MK Bolla, Q (Qing) Wang, J Dennis, EJ Sawyer, T Cheng, I Tomlinson, MJ Kerin, N Miller, F Marme, HM Surowy, B Burwinkel, P Guenel, T Truong, F Menegaux, C Mulot, SE Bojesen, BG Nordestgaard, SF Nielsen, H Flyger, J Benitez, MP Zamora, JIA Perez, P Menendez, A Gonzalez-Neira, G Pita, MR Alonso, N Alvarez, D Herrera, H Anton-Culver, H Brenner, AK Dieffenbach, V Arndt, C Stegmaier, A Meindl, P Lichtner, RK Schmutzler, B Muller-Myhsok, H Brauch, T Bruning, YD Ko, DC Tessier, D Vincent, F Bacot, H Nevanlinna, K Aittomaki, C Blomqvist, Salima Khan, K Matsuo, H Ito, H Iwata, A Horio, NV Bogdanova, NN Antonenkova, T Dork, A Lindblom, S Margolin, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, AH Wu, CC Tseng, D van den Berg, DO Stram, P Neven, Erwin Wauters, H Wildiers, D Lambrechts, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, P Radice, P Peterlongo, S Manoukian, B Bonanni, FJ Couch, XS Wang, C Vachon, K Purrington, GG Giles, RL Milne, C McLean, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, J Simard, MS Goldberg, F Labreche, M Dumont, SH Teo, CH Yip, N Hassan, EN Vithana, V Kristensen, W Zheng, S Deming-Halverson, MJ Shrubsole, JR Long, R Winqvist, K Pylkas, A Jukkola-Vuorinen, S Kauppila, IL Andrulis, JA Knight, G Glendon, S Tchatchou, P Devilee, RAEM Tollenaar, Caroline Seynaeve, CJ van Asperen, M Garcia-Closas, J Figueroa, J Lissowska, L Brinton, K Czene, H Darabi, M Eriksson, JS Brand, Maartje Hooning, Antoinette Hollestelle, Ans van den Ouweland, Agnes Jager, JM Li, JJ Liu, K Humphreys, XO Shu, W Lu, YT Gao, H Cai, SS Cross, MWR Reed, W Blot, LB Signorello, QY Cai, PDP Pharoah, B Perkins, M Shah, FM Blows, D Kang, KY Yoo, DY Noh, M Hartman, H Miao, KS Chia, TC Putti, U Hamann, C Luccarini, C Baynes, S (Shahana) Ahmed, M Maranian, CS Healey, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, S Sangrajrang, V Gaborieau, P Brennan, J Mckay, S Slager, AE Toland, D Yannoukakos, CY Shen, CN Hsiung, PE Wu, SL Ding, A Ashworth, M Jones, N Orr, AJ Swerdlow, H Tsimiklis, E Makalic, DF Schmidt, QM Bui, SJ Chanock, DJ Hunter, R Hein, N Dahmen, L Beckmann, K Aaltonen, TA Muranen, T Heikkinen, A Irwanto, N Rahman, CA Turnbull, Q Waisfisz, HEJ Meijers-Heijboer, MA (Muriel) Adank, RB van der Luijt, P Hall, G Chenevix-Trench, A Dunning, DF Easton, A Cox

Research output: Contribution to journal › Article › Academic › peer-review

37 Citations (Scopus)

Abstract

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 regression models 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, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 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 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Original language	Undefined/Unknown
Pages (from-to)	285-298
Number of pages	14
Journal	Human Molecular Genetics
Volume	24
Issue number	1
DOIs	https://doi.org/10.1093/hmg/ddu431
Publication status	Published - 2015

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10.1093/hmg/ddu431

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Lin, WY., Camp, NJ., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, JL., Apicella, C., Southey, MC., Stone, J., Schmidt, MK., Broeks, A., van 't Veer, LJ., Rutgers, EJT., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, PA., Haeberle, L., ... 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), 285-298. https://doi.org/10.1093/hmg/ddu431

Lin, WY ; Camp, NJ ; Ghoussaini, M ; Beesley, J ; Michailidou, K ; Hopper, JL ; Apicella, C ; Southey, MC ; Stone, J ; Schmidt, MK (Marjanka) ; Broeks, A ; van 't Veer, LJ (Laura) ; Rutgers, EJT ; Muir, K ; Lophatananon, A ; Stewart-Brown, S ; Siriwanarangsan, P ; Fasching, PA ; Haeberle, L ; Ekici, AB ; Beckmann, MW ; Peto, J ; dos-Santos-Silva, I ; Fletcher, O ; Johnson, N ; Bolla, MK ; Wang, Q (Qing) ; Dennis, J ; Sawyer, EJ ; Cheng, T ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Marme, F ; Surowy, HM ; Burwinkel, B ; Guenel, P ; Truong, T ; Menegaux, F ; Mulot, C ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Benitez, J ; Zamora, MP ; Perez, JIA ; Menendez, P ; Gonzalez-Neira, A ; Pita, G ; Alonso, MR ; Alvarez, N ; Herrera, D ; Anton-Culver, H ; Brenner, H ; Dieffenbach, AK ; Arndt, V ; Stegmaier, C ; Meindl, A ; Lichtner, P ; Schmutzler, RK ; Muller-Myhsok, B ; Brauch, H ; Bruning, T ; Ko, YD ; Tessier, DC ; Vincent, D ; Bacot, F ; Nevanlinna, H ; Aittomaki, K ; Blomqvist, C ; Khan, Salima ; Matsuo, K ; Ito, H ; Iwata, H ; Horio, A ; Bogdanova, NV ; Antonenkova, NN ; Dork, T ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, VM ; Hartikainen, JM ; Wu, AH ; Tseng, CC ; van den Berg, D ; Stram, DO ; Neven, P ; Wauters, Erwin ; Wildiers, H ; Lambrechts, D ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Radice, P ; Peterlongo, P ; Manoukian, S ; Bonanni, B ; Couch, FJ ; Wang, XS ; Vachon, C ; Purrington, K ; Giles, GG ; Milne, RL ; McLean, C ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Simard, J ; Goldberg, MS ; Labreche, F ; Dumont, M ; Teo, SH ; Yip, CH ; Hassan, N ; Vithana, EN ; Kristensen, V ; Zheng, W ; Deming-Halverson, S ; Shrubsole, MJ ; Long, JR ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Kauppila, S ; Andrulis, IL ; Knight, JA ; Glendon, G ; Tchatchou, S ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, Caroline ; van Asperen, CJ ; Garcia-Closas, M ; Figueroa, J ; Lissowska, J ; Brinton, L ; Czene, K ; Darabi, H ; Eriksson, M ; Brand, JS ; Hooning, Maartje ; Hollestelle, Antoinette ; van den Ouweland, Ans ; Jager, Agnes ; Li, JM ; Liu, JJ ; Humphreys, K ; Shu, XO ; Lu, W ; Gao, YT ; Cai, H ; Cross, SS ; Reed, MWR ; Blot, W ; Signorello, LB ; Cai, QY ; Pharoah, PDP ; Perkins, B ; Shah, M ; Blows, FM ; Kang, D ; Yoo, KY ; Noh, DY ; Hartman, M ; Miao, H ; Chia, KS ; Putti, TC ; Hamann, U ; Luccarini, C ; Baynes, C ; Ahmed, S (Shahana) ; Maranian, M ; Healey, CS ; Jakubowska, A ; Lubinski, J ; Jaworska-Bieniek, K ; Durda, K ; Sangrajrang, S ; Gaborieau, V ; Brennan, P ; Mckay, J ; Slager, S ; Toland, AE ; Yannoukakos, D ; Shen, CY ; Hsiung, CN ; Wu, PE ; Ding, SL ; Ashworth, A ; Jones, M ; Orr, N ; Swerdlow, AJ ; Tsimiklis, H ; Makalic, E ; Schmidt, DF ; Bui, QM ; Chanock, SJ ; Hunter, DJ ; Hein, R ; Dahmen, N ; Beckmann, L ; Aaltonen, K ; Muranen, TA ; Heikkinen, T ; Irwanto, A ; Rahman, N ; Turnbull, CA ; Waisfisz, Q ; Meijers-Heijboer, HEJ ; Adank, MA (Muriel) ; van der Luijt, RB ; Hall, P ; Chenevix-Trench, G ; Dunning, A ; Easton, DF ; Cox, A. / Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 1. pp. 285-298.

@article{80d5c2f1aebf4faa8c37099150fee47f,

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

abstract = "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 regression models 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, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 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 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.",

author = "WY Lin and NJ Camp and M Ghoussaini and J Beesley and K Michailidou and JL Hopper and C Apicella and MC Southey and J Stone and Schmidt, {MK (Marjanka)} and A Broeks and {van 't Veer}, {LJ (Laura)} and EJT Rutgers and K Muir and A Lophatananon and S Stewart-Brown and P Siriwanarangsan and PA Fasching and L Haeberle and AB Ekici and MW Beckmann and J Peto and I dos-Santos-Silva and O Fletcher and N Johnson and MK Bolla and Wang, {Q (Qing)} and J Dennis and EJ Sawyer and T Cheng and I Tomlinson and MJ Kerin and N Miller and F Marme and HM Surowy and B Burwinkel and P Guenel and T Truong and F Menegaux and C Mulot and SE Bojesen and BG Nordestgaard and SF Nielsen and H Flyger and J Benitez and MP Zamora and JIA Perez and P Menendez and A Gonzalez-Neira and G Pita and MR Alonso and N Alvarez and D Herrera and H Anton-Culver and H Brenner and AK Dieffenbach and V Arndt and C Stegmaier and A Meindl and P Lichtner and RK Schmutzler and B Muller-Myhsok and H Brauch and T Bruning and YD Ko and DC Tessier and D Vincent and F Bacot and H Nevanlinna and K Aittomaki and C Blomqvist and Salima Khan and K Matsuo and H Ito and H Iwata and A Horio and NV Bogdanova and NN Antonenkova and T Dork and A Lindblom and S Margolin and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and AH Wu and CC Tseng and {van den Berg}, D and DO Stram and P Neven and Erwin Wauters and H Wildiers and D Lambrechts and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and P Radice and P Peterlongo and S Manoukian and B Bonanni and FJ Couch and XS Wang and C Vachon and K Purrington and GG Giles and RL Milne and C McLean and CA Haiman and BE Henderson and F Schumacher and {Le Marchand}, L and J Simard and MS Goldberg and F Labreche and M Dumont and SH Teo and CH Yip and N Hassan and EN Vithana and V Kristensen and W Zheng and S Deming-Halverson and MJ Shrubsole and JR Long and R Winqvist and K Pylkas and A Jukkola-Vuorinen and S Kauppila and IL Andrulis and JA Knight and G Glendon and S Tchatchou and P Devilee and RAEM Tollenaar and Caroline Seynaeve and {van Asperen}, CJ and M Garcia-Closas and J Figueroa and J Lissowska and L Brinton and K Czene and H Darabi and M Eriksson and JS Brand and Maartje Hooning and Antoinette Hollestelle and {van den Ouweland}, Ans and Agnes Jager and JM Li and JJ Liu and K Humphreys and XO Shu and W Lu and YT Gao and H Cai and SS Cross and MWR Reed and W Blot and LB Signorello and QY Cai and PDP Pharoah and B Perkins and M Shah and FM Blows and D Kang and KY Yoo and DY Noh and M Hartman and H Miao and KS Chia and TC Putti and U Hamann and C Luccarini and C Baynes and Ahmed, {S (Shahana)} and M Maranian and CS Healey and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and S Sangrajrang and V Gaborieau and P Brennan and J Mckay and S Slager and AE Toland and D Yannoukakos and CY Shen and CN Hsiung and PE Wu and SL Ding and A Ashworth and M Jones and N Orr and AJ Swerdlow and H Tsimiklis and E Makalic and DF Schmidt and QM Bui and SJ Chanock and DJ Hunter and R Hein and N Dahmen and L Beckmann and K Aaltonen and TA Muranen and T Heikkinen and A Irwanto and N Rahman and CA Turnbull and Q Waisfisz and HEJ Meijers-Heijboer and Adank, {MA (Muriel)} and {van der Luijt}, RB and P Hall and G Chenevix-Trench and A Dunning and DF Easton and A Cox",

year = "2015",

doi = "10.1093/hmg/ddu431",

language = "Undefined/Unknown",

volume = "24",

pages = "285--298",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "1",

}

Lin, WY, Camp, NJ, Ghoussaini, M, Beesley, J, Michailidou, K, Hopper, JL, Apicella, C, Southey, MC, Stone, J, Schmidt, MK, Broeks, A, van 't Veer, LJ, Rutgers, EJT, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Wang, Q, Dennis, J, Sawyer, EJ, Cheng, T, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Surowy, HM, Burwinkel, B, Guenel, P, Truong, T, Menegaux, F, Mulot, C, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrera, D, Anton-Culver, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Muller-Myhsok, B, Brauch, H, Bruning, T, Ko, YD, Tessier, DC, Vincent, D, Bacot, F, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Khan, S, Matsuo, K, Ito, H, Iwata, H, Horio, A, Bogdanova, NV, Antonenkova, NN, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, 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, FJ, Wang, XS, Vachon, C, Purrington, K, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, Hassan, N, Vithana, EN, Kristensen, V, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, JR, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Lissowska, J, Brinton, L, Czene, K, Darabi, H, Eriksson, M, Brand, JS, Hooning, M , Hollestelle, A , van den Ouweland, A , Jager, A, Li, JM, Liu, JJ, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Pharoah, PDP, Perkins, B, Shah, M, Blows, FM, Kang, D, Yoo, KY, Noh, DY, Hartman, M, Miao, H, Chia, KS, Putti, TC, Hamann, U, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Hsiung, CN, Wu, PE, Ding, SL, Ashworth, A, Jones, M, Orr, N, Swerdlow, AJ, Tsimiklis, H, Makalic, E, Schmidt, DF, Bui, QM, Chanock, SJ, Hunter, DJ, Hein, R, Dahmen, N, Beckmann, L, Aaltonen, K, Muranen, TA, Heikkinen, T, Irwanto, A, Rahman, N, Turnbull, CA, Waisfisz, Q, Meijers-Heijboer, HEJ, Adank, MA, van der Luijt, RB, Hall, P, Chenevix-Trench, G, Dunning, A, Easton, DF & Cox, A 2015, 'Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk', Human Molecular Genetics, vol. 24, no. 1, pp. 285-298. https://doi.org/10.1093/hmg/ddu431

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. / Lin, WY; Camp, NJ; Ghoussaini, M; Beesley, J; Michailidou, K; Hopper, JL; Apicella, C; Southey, MC; Stone, J; Schmidt, MK (Marjanka); Broeks, A; van 't Veer, LJ (Laura); Rutgers, EJT; Muir, K; Lophatananon, A; Stewart-Brown, S; Siriwanarangsan, P; Fasching, PA; Haeberle, L; Ekici, AB; Beckmann, MW; Peto, J; dos-Santos-Silva, I; Fletcher, O; Johnson, N; Bolla, MK; Wang, Q (Qing); Dennis, J; Sawyer, EJ; Cheng, T; Tomlinson, I; Kerin, MJ; Miller, N; Marme, F; Surowy, HM; Burwinkel, B; Guenel, P; Truong, T; Menegaux, F; Mulot, C; Bojesen, SE; Nordestgaard, BG; Nielsen, SF; Flyger, H; Benitez, J; Zamora, MP; Perez, JIA; Menendez, P; Gonzalez-Neira, A; Pita, G; Alonso, MR; Alvarez, N; Herrera, D; Anton-Culver, H; Brenner, H; Dieffenbach, AK; Arndt, V; Stegmaier, C; Meindl, A; Lichtner, P; Schmutzler, RK; Muller-Myhsok, B; Brauch, H; Bruning, T; Ko, YD; Tessier, DC; Vincent, D; Bacot, F; Nevanlinna, H; Aittomaki, K; Blomqvist, C; Khan, Salima; Matsuo, K; Ito, H; Iwata, H; Horio, A; Bogdanova, NV; Antonenkova, NN; Dork, T; Lindblom, A; Margolin, S; Mannermaa, A; Kataja, V; Kosma, VM; Hartikainen, JM; Wu, AH; Tseng, CC; van den Berg, D; Stram, DO; Neven, P; Wauters, Erwin; Wildiers, H; Lambrechts, D; Chang-Claude, J; Rudolph, A; Seibold, P; Flesch-Janys, D; Radice, P; Peterlongo, P; Manoukian, S; Bonanni, B; Couch, FJ; Wang, XS; Vachon, C; Purrington, K; Giles, GG; Milne, RL; McLean, C; Haiman, CA; Henderson, BE; Schumacher, F; Le Marchand, L; Simard, J; Goldberg, MS; Labreche, F; Dumont, M; Teo, SH; Yip, CH; Hassan, N; Vithana, EN; Kristensen, V; Zheng, W; Deming-Halverson, S; Shrubsole, MJ; Long, JR; Winqvist, R; Pylkas, K; Jukkola-Vuorinen, A; Kauppila, S; Andrulis, IL; Knight, JA; Glendon, G; Tchatchou, S; Devilee, P; Tollenaar, RAEM; Seynaeve, Caroline; van Asperen, CJ; Garcia-Closas, M; Figueroa, J; Lissowska, J; Brinton, L; Czene, K; Darabi, H; Eriksson, M; Brand, JS; Hooning, Maartje ; Hollestelle, Antoinette ; van den Ouweland, Ans ; Jager, Agnes; Li, JM; Liu, JJ; Humphreys, K; Shu, XO; Lu, W; Gao, YT; Cai, H; Cross, SS; Reed, MWR; Blot, W; Signorello, LB; Cai, QY; Pharoah, PDP; Perkins, B; Shah, M; Blows, FM; Kang, D; Yoo, KY; Noh, DY; Hartman, M; Miao, H; Chia, KS; Putti, TC; Hamann, U; Luccarini, C; Baynes, C; Ahmed, S (Shahana); Maranian, M; Healey, CS; Jakubowska, A; Lubinski, J; Jaworska-Bieniek, K; Durda, K; Sangrajrang, S; Gaborieau, V; Brennan, P; Mckay, J; Slager, S; Toland, AE; Yannoukakos, D; Shen, CY; Hsiung, CN; Wu, PE; Ding, SL; Ashworth, A; Jones, M; Orr, N; Swerdlow, AJ; Tsimiklis, H; Makalic, E; Schmidt, DF; Bui, QM; Chanock, SJ; Hunter, DJ; Hein, R; Dahmen, N; Beckmann, L; Aaltonen, K; Muranen, TA; Heikkinen, T; Irwanto, A; Rahman, N; Turnbull, CA; Waisfisz, Q; Meijers-Heijboer, HEJ; Adank, MA (Muriel); van der Luijt, RB; Hall, P; Chenevix-Trench, G; Dunning, A; Easton, DF; Cox, A.

In: Human Molecular Genetics, Vol. 24, No. 1, 2015, p. 285-298.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

AU - Lin, WY

AU - Camp, NJ

AU - Ghoussaini, M

AU - Beesley, J

AU - Michailidou, K

AU - Hopper, JL

AU - Apicella, C

AU - Southey, MC

AU - Stone, J

AU - Schmidt, MK (Marjanka)

AU - Broeks, A

AU - van 't Veer, LJ (Laura)

AU - Rutgers, EJT

AU - Muir, K

AU - Lophatananon, A

AU - Stewart-Brown, S

AU - Siriwanarangsan, P

AU - Fasching, PA

AU - Haeberle, L

AU - Ekici, AB

AU - Beckmann, MW

AU - Peto, J

AU - dos-Santos-Silva, I

AU - Fletcher, O

AU - Johnson, N

AU - Bolla, MK

AU - Wang, Q (Qing)

AU - Dennis, J

AU - Sawyer, EJ

AU - Cheng, T

AU - Tomlinson, I

AU - Kerin, MJ

AU - Miller, N

AU - Marme, F

AU - Surowy, HM

AU - Burwinkel, B

AU - Guenel, P

AU - Truong, T

AU - Menegaux, F

AU - Mulot, C

AU - Bojesen, SE

AU - Nordestgaard, BG

AU - Nielsen, SF

AU - Flyger, H

AU - Benitez, J

AU - Zamora, MP

AU - Perez, JIA

AU - Menendez, P

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, MR

AU - Alvarez, N

AU - Herrera, D

AU - Anton-Culver, H

AU - Brenner, H

AU - Dieffenbach, AK

AU - Arndt, V

AU - Stegmaier, C

AU - Meindl, A

AU - Lichtner, P

AU - Schmutzler, RK

AU - Muller-Myhsok, B

AU - Brauch, H

AU - Bruning, T

AU - Ko, YD

AU - Tessier, DC

AU - Vincent, D

AU - Bacot, F

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Blomqvist, C

AU - Khan, Salima

AU - Matsuo, K

AU - Ito, H

AU - Iwata, H

AU - Horio, A

AU - Bogdanova, NV

AU - Antonenkova, NN

AU - Dork, T

AU - Lindblom, A

AU - Margolin, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Wu, AH

AU - Tseng, CC

AU - van den Berg, D

AU - Stram, DO

AU - Neven, P

AU - Wauters, Erwin

AU - Wildiers, H

AU - Lambrechts, D

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Radice, P

AU - Peterlongo, P

AU - Manoukian, S

AU - Bonanni, B

AU - Couch, FJ

AU - Wang, XS

AU - Vachon, C

AU - Purrington, K

AU - Giles, GG

AU - Milne, RL

AU - McLean, C

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, F

AU - Le Marchand, L

AU - Simard, J

AU - Goldberg, MS

AU - Labreche, F

AU - Dumont, M

AU - Teo, SH

AU - Yip, CH

AU - Hassan, N

AU - Vithana, EN

AU - Kristensen, V

AU - Zheng, W

AU - Deming-Halverson, S

AU - Shrubsole, MJ

AU - Long, JR

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Kauppila, S

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Tchatchou, S

AU - Devilee, P

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - van Asperen, CJ

AU - Garcia-Closas, M

AU - Figueroa, J

AU - Lissowska, J

AU - Brinton, L

AU - Czene, K

AU - Darabi, H

AU - Eriksson, M

AU - Brand, JS

AU - Hooning, Maartje

AU - Hollestelle, Antoinette

AU - van den Ouweland, Ans

AU - Jager, Agnes

AU - Li, JM

AU - Liu, JJ

AU - Humphreys, K

AU - Shu, XO

AU - Lu, W

AU - Gao, YT

AU - Cai, H

AU - Cross, SS

AU - Reed, MWR

AU - Blot, W

AU - Signorello, LB

AU - Cai, QY

AU - Pharoah, PDP

AU - Perkins, B

AU - Shah, M

AU - Blows, FM

AU - Kang, D

AU - Yoo, KY

AU - Noh, DY

AU - Hartman, M

AU - Miao, H

AU - Chia, KS

AU - Putti, TC

AU - Hamann, U

AU - Luccarini, C

AU - Baynes, C

AU - Ahmed, S (Shahana)

AU - Maranian, M

AU - Healey, CS

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Sangrajrang, S

AU - Gaborieau, V

AU - Brennan, P

AU - Mckay, J

AU - Slager, S

AU - Toland, AE

AU - Yannoukakos, D

AU - Shen, CY

AU - Hsiung, CN

AU - Wu, PE

AU - Ding, SL

AU - Ashworth, A

AU - Jones, M

AU - Orr, N

AU - Swerdlow, AJ

AU - Tsimiklis, H

AU - Makalic, E

AU - Schmidt, DF

AU - Bui, QM

AU - Chanock, SJ

AU - Hunter, DJ

AU - Hein, R

AU - Dahmen, N

AU - Beckmann, L

AU - Aaltonen, K

AU - Muranen, TA

AU - Heikkinen, T

AU - Irwanto, A

AU - Rahman, N

AU - Turnbull, CA

AU - Waisfisz, Q

AU - Meijers-Heijboer, HEJ

AU - Adank, MA (Muriel)

AU - van der Luijt, RB

AU - Hall, P

AU - Chenevix-Trench, G

AU - Dunning, A

AU - Easton, DF

AU - Cox, A

PY - 2015

Y1 - 2015

N2 - 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 regression models 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, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 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 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

AB - 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 regression models 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, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 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 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

U2 - 10.1093/hmg/ddu431

DO - 10.1093/hmg/ddu431

M3 - Article

VL - 24

SP - 285

EP - 298

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 1

ER -