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

N.J. Camp; M. Ghoussaini; J. Beesley; K. Michailidou; J.L. Hopper; C. Apicella; M.C. Southey; Jennifer Stone; M.K. Schmidt; A. Broeks; L.J. Van'T Veer; E.J. Th Rutgers; K. Muir; A. Lophatananon; S. Stewart-Brown; P. Siriwanarangsan; P.A. Fasching; L. Haeberle; A.B. Ekici; M.W. Beckmann; J. Peto; I. Dos-Santos-Silva; O. Fletcher; N. Johnson; M.K. Bolla; Q. Wang; J. Dennis; E.J. Sawyer; T. Cheng; I. Tomlinson; M.J. Kerin; N. Miller; F. Marmé; H.M. Surowy; B. Burwinkel; P. Guénel; T. Truong; F. Menegaux; C. Mulot; S.E. Bojesen; B.G. Nordestgaard; S.F. Nielsen; H. Flyger; J. Benitez; M. Pilar Zamora; J.I.A. Perez; P. Menéndez; A. González-Neira; G. Pita; M. Rosario Alonso; N. Álvarez; D. Herrero; H. Anton-Culver; H. Brenner; A.K. Dieffenbach; V. Arndt; C. Stegmaier; A. Meindl; P. Lichtner; R.K. Schmutzler; B. Müller-Myhsok; H. Brauch; T. Brüning; Y.D. Ko; D.C. Tessier; D. Vincent; F. Bacot; H. Nevanlinna; K. Aittomäki; C. Blomqvist; S. Khan; K. Matsuo; H. Ito; H. Iwata; A. Horio; N.V. Bogdanova

doi:10.1093/hmg/ddu431

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

N.J. Camp, M. Ghoussaini, J. Beesley, K. Michailidou, J.L. Hopper, C. Apicella, M.C. Southey, Jennifer Stone, M.K. Schmidt, A. Broeks, L.J. Van'T Veer, E.J. Th Rutgers, K. Muir, A. Lophatananon, S. Stewart-Brown, P. Siriwanarangsan, P.A. Fasching, L. Haeberle, A.B. Ekici, M.W. BeckmannJ. Peto, I. Dos-Santos-Silva, O. Fletcher, N. Johnson, M.K. Bolla, Q. Wang, J. Dennis, E.J. Sawyer, T. Cheng, I. Tomlinson, M.J. Kerin, N. Miller, F. Marmé, H.M. Surowy, B. Burwinkel, P. Guénel, T. Truong, F. Menegaux, C. Mulot, S.E. Bojesen, B.G. Nordestgaard, S.F. Nielsen, H. Flyger, J. Benitez, M. Pilar Zamora, J.I.A. Perez, P. Menéndez, A. González-Neira, G. Pita, M. Rosario Alonso, N. Álvarez, D. Herrero, H. Anton-Culver, H. Brenner, A.K. Dieffenbach, V. Arndt, C. Stegmaier, A. Meindl, P. Lichtner, R.K. Schmutzler, B. Müller-Myhsok, H. Brauch, T. Brüning, Y.D. Ko, D.C. Tessier, D. Vincent, F. Bacot, H. Nevanlinna, K. Aittomäki, C. Blomqvist, S. Khan, K. Matsuo, H. Ito, H. Iwata, A. Horio, N.V. Bogdanova

Centre for Genetic Origins of Health and Diseases

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37 Citations (Scopus)

Abstract

© The Author 2014. 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.

Original language	English
Pages (from-to)	285-298
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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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., ... Bogdanova, N. V. (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

@article{3c999228d7ba435593ccbe126baf4ed7,

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

abstract = "{\textcopyright} The Author 2014. 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.",

author = "N.J. Camp and M. Ghoussaini and J. Beesley and K. Michailidou and J.L. Hopper and C. Apicella and M.C. Southey and Jennifer Stone and M.K. Schmidt and A. Broeks and {Van'T Veer}, L.J. and {Th Rutgers}, E.J. and K. Muir and A. Lophatananon and S. Stewart-Brown and P. Siriwanarangsan and P.A. Fasching and L. Haeberle and A.B. Ekici and M.W. Beckmann and J. Peto and I. Dos-Santos-Silva and O. Fletcher and N. Johnson and M.K. Bolla and Q. Wang and J. Dennis and E.J. Sawyer and T. Cheng and I. Tomlinson and M.J. Kerin and N. Miller and F. Marm{\'e} and H.M. Surowy and B. Burwinkel and P. Gu{\'e}nel and T. Truong and F. Menegaux and C. Mulot and S.E. Bojesen and B.G. Nordestgaard and S.F. Nielsen and H. Flyger and J. Benitez and {Pilar Zamora}, M. and J.I.A. Perez and P. Men{\'e}ndez and A. Gonz{\'a}lez-Neira and G. Pita and {Rosario Alonso}, M. and N. {\'A}lvarez and D. Herrero and H. Anton-Culver and H. Brenner and A.K. Dieffenbach and V. Arndt and C. Stegmaier and A. Meindl and P. Lichtner and R.K. Schmutzler and B. M{\"u}ller-Myhsok and H. Brauch and T. Br{\"u}ning and Y.D. Ko and D.C. Tessier and D. Vincent and F. Bacot and H. Nevanlinna and K. Aittom{\"a}ki and C. Blomqvist and S. Khan and K. Matsuo and H. Ito and H. Iwata and A. Horio and N.V. Bogdanova",

year = "2015",

doi = "10.1093/hmg/ddu431",

language = "English",

volume = "24",

pages = "285--298",

journal = "Human Molecular Genetics",

issn = "1460-2083",

publisher = "Oxford University Press",

number = "1",

}

Camp, NJ, Ghoussaini, M, Beesley, J, Michailidou, K, Hopper, JL, Apicella, C, Southey, MC, Stone, J, Schmidt, MK, Broeks, A, Van'T Veer, LJ, Th Rutgers, EJ, 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, Marmé, F, Surowy, HM, Burwinkel, B, Guénel, P, Truong, T, Menegaux, F, Mulot, C, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Anton-Culver, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Müller-Myhsok, B, Brauch, H, Brüning, T, Ko, YD, Tessier, DC, Vincent, D, Bacot, F, Nevanlinna, H, Aittomäki, K, Blomqvist, C, Khan, S, Matsuo, K, Ito, H, Iwata, H, Horio, A & Bogdanova, NV 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

TY - JOUR

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

AU - Camp, N.J.

AU - Ghoussaini, M.

AU - Beesley, J.

AU - Michailidou, K.

AU - Hopper, J.L.

AU - Apicella, C.

AU - Southey, M.C.

AU - Stone, Jennifer

AU - Schmidt, M.K.

AU - Broeks, A.

AU - Van'T Veer, L.J.

AU - Th Rutgers, E.J.

AU - Muir, K.

AU - Lophatananon, A.

AU - Stewart-Brown, S.

AU - Siriwanarangsan, P.

AU - Fasching, P.A.

AU - Haeberle, L.

AU - Ekici, A.B.

AU - Beckmann, M.W.

AU - Peto, J.

AU - Dos-Santos-Silva, I.

AU - Fletcher, O.

AU - Johnson, N.

AU - Bolla, M.K.

AU - Wang, Q.

AU - Dennis, J.

AU - Sawyer, E.J.

AU - Cheng, T.

AU - Tomlinson, I.

AU - Kerin, M.J.

AU - Miller, N.

AU - Marmé, F.

AU - Surowy, H.M.

AU - Burwinkel, B.

AU - Guénel, P.

AU - Truong, T.

AU - Menegaux, F.

AU - Mulot, C.

AU - Bojesen, S.E.

AU - Nordestgaard, B.G.

AU - Nielsen, S.F.

AU - Flyger, H.

AU - Benitez, J.

AU - Pilar Zamora, M.

AU - Perez, J.I.A.

AU - Menéndez, P.

AU - González-Neira, A.

AU - Pita, G.

AU - Rosario Alonso, M.

AU - Álvarez, N.

AU - Herrero, D.

AU - Anton-Culver, H.

AU - Brenner, H.

AU - Dieffenbach, A.K.

AU - Arndt, V.

AU - Stegmaier, C.

AU - Meindl, A.

AU - Lichtner, P.

AU - Schmutzler, R.K.

AU - Müller-Myhsok, B.

AU - Brauch, H.

AU - Brüning, T.

AU - Ko, Y.D.

AU - Tessier, D.C.

AU - Vincent, D.

AU - Bacot, F.

AU - Nevanlinna, H.

AU - Aittomäki, K.

AU - Blomqvist, C.

AU - Khan, S.

AU - Matsuo, K.

AU - Ito, H.

AU - Iwata, H.

AU - Horio, A.

AU - Bogdanova, N.V.

PY - 2015

Y1 - 2015

N2 - © The Author 2014. 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.

AB - © The Author 2014. 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.

U2 - 10.1093/hmg/ddu431

DO - 10.1093/hmg/ddu431

M3 - Article

C2 - 25168388

SN - 1460-2083

VL - 24

SP - 285

EP - 298

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

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

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