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

Author

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., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Li, J.M., 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.X., 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., Ouweland, A.M.W. van den, Koppert, L.B., Fletcher, O., Johnson, N., Dos-Santos-Silva, I., Peto, J., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., 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.R., 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.Y., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Wu, A.H., Tseng, C.C., Berg, D. van den, 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.S., Olson, J.E., Vachon, C., Purrington, K., Severi, G., Baglietto, L., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Czene, K., Eriksson, M., Humphreys, K., Darabi, H., Ahmed, S., Shah, M., Pharoah, P.D.P., Hall, P., Giles, G.G., Benitez, J., Dunning, A.M., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, TNBCC, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Adult, Ataxin-7, A Kinase Anchor Proteins, Breast Neoplasms, Nerve Tissue Proteins, Middle Aged, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Cytoskeletal Proteins, Case-Control Studies, Humans, NIMA-Related Kinases, Female, Genetic Predisposition to Disease, health care economics and organizations, Alleles, Genome-Wide Association Study
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility\ud variants, although most studies have been underpowered to detect associations of a realistic magnitude.\ud We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which\ud evidence of association with breast cancer risk had been previously reported. Case-control data were combined\ud from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional\ud logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21\ud [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026\ud ], AKAP9-M463I at\ud 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026\ud ) and NEK10-L513S at 3p24 (rs10510592,\ud 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\ud significance in a combined analysis of available data, including independent data from nine genome-wide association\ud studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028\ud ); for AKAP9-M463I,\ud 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\ud regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified\ud a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is\ud associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility\ud region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of\ud the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast\ud cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying\ud variants and the genes through which they act.

Published
2014

2. Fine-scale mapping of the 4q24 locus identifies & pr two Independent loci associated with breast cancer risk

Author

Guo, X. (Xingyi), Long, J. (Jirong), Zeng, C. (Chenjie), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Milne, R.L. (Roger L.), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Beesley, J. (Jonathan), Kar, S. (Siddhartha), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Broekss, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, H. (Hui), Canisius, S. (Sander), Chang-Claude, J. (Jenny), Choi, J.-Y. (J.), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Droit, A. (Arnaud), Dörk, T. (Thilo), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Gaborieau, V. (Valerie), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Grip, M. (Mervi), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hamann, U. (Ute), Hartman, J.M. (Joost), Hollestelle, A. (Antoinette), Hopper, J.L. (John L.), Hsiung, C.-N. (Chia-Ni), Ito, H. (Hidemi), Jakubowska, A. (Anna), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Khan, S. (Sofia), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federick), Matsuo, K. (Keitaro), McLean, C.A. (Catriona Ann), Meindl, A. (Alfons), Muir, K. (Kenneth), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Olson, J.E. (Janet), Orr, N. (Nick), Peterlongo, P. (Paolo), Putti, T.C. (Thomas Choudary), Rudolph, A. (Anja), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Shen, C-Y. (Chen-Yang), Shi, J. (Jiajun), Shrubsole, M. (Martha), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Thienpont, B. (Bernard), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-chen), Ouweland, A.M.W. (Ans) van den, Wen, W. (Wanqing), Winqvist, R. (Robert), Wu, A. (Anna), Yip, C.H. (Cheng Har), Zamora, M.P. (Pilar), Zheng, Y. (Ying), Hall, P. (Per), Pharoah, P.D.P. (Paul), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Easton, D.F. (Douglas F.), Zheng, W. (Wei), Eeles, R. (Rosalind), Al Olama, A.A. (Ali Amin), Kote-Jarai, Z., Benlloch, S. (Sara), Antoniou, A.C. (Antonis), McGuffog, L. (Lesley), Offit, K. (Kenneth), Lee, A. (Andrew), Dicks, E. (Ed), Luccarini, C. (Craig), Tessier, D.C. (Daniel C.), Bacot, F. (Francois), Vincent, D. (Daniel), La Boissière, S. (Sylvie), Robidoux, F. (Frederic), Nielsen, S.F. (Sune), Cunningham, J.M. (Julie), Windebank, S.A. (Sharon A.), Hilker, C.A. (Christopher A.), Meyer, J. (Jeffrey), Angelakos, M. (Maggie), Maskiell, J. (Judi), Rutgers, E.J. (Emiel J.), Verhoef, S., Hogervorst, F.B.L. (Frans), Boonyawongviroj, P. (Prat), Siriwanarungsan, P. (Pornthep), Schrauder, A. (André), Rübner, M. (Matthias), Oeser, S. (Sonja), Landrith, S. (Silke), Williams, E. (Eileen), Ryder-Mills, E. (Elaine), Sargus, K. (Kara), McInerney, N. (Niall), Colleran, G. (Gabrielle), Rowan, A. (Andrew), Jones, A. (Angela), Sohn, C. (Christof), Schneeweiß, A. (Andeas), Bugert, P. (Peter), Álvarez, N. (Nuria), Bernstein, L. (Leslie), Lacey, J. (James), Wang, S. (Sophia), Ma, H. (Huiyan), Lu, Y. (Yani), Clague De Hart, J. (Jessica), Deapen, D. (Dennis), Pinder, R. (Rich), Lee, E. (Eunjung), Schumacher, F.R. (Fredrick), Horn-Ross, P. (Pam), Reynolds, P. (Peggy), Nelson, D. (David), Park, H. (Hannah), Ziegler, H. (Hartwig), Wolf, S. (Sonja), Hermann, V. (Volker), Lo, W.-Y. (Wing-Yee), Justenhoven, C. (Christina), Ko, Y.-D. (Yon-Dschun), Baisch, C. (Christian), Fischer, H.-P. (Hans-Peter), Pesch, B. (Beate), Rabstein, S. (Sylvia), Lotz, A. (Anne), Harth, V. (Volker), Heikkinen, T. (Tuomas), Erkkilä, I. (Irja), Aaltonen, K. (Kirsimari), Smitten, K. (Karl) von, Antonenkova, N.N. (Natalia), Hillemanns, P. (Peter), Christiansen, H. (Hans), Myöhänen, E. (Eija), Kemiläinen, H. (Helena), Thorne, H. (Heather), Niedermayr, E. (Eveline), Bowtell, D., De Fazio, A. (Anna), Gertig, D., Green, A., Webb, P. (Penny), Parsons, P., Hayward, N., Webb, P.M. (P.), Whiteman, D., Fung, A. (Annie), Yashiki, J. (June), Peuteman, G. (Gilian), Smeets, D. (Dominiek), Van Brussel, T. (Thomas), Corthouts, K. (Kathleen), Obi, N. (Nadia), Heinz, J. (Judith), Behrens, T.W. (Timothy), Eilber, U. (Ursula), Celik, M. (Muhabbet), Olchers, T. (Til), Peissel, B. (Bernard), Scuvera, G. (Giulietta), Zaffaroni, D. (Daniela), Bonnani, B. (Bernardo), Feroce, I. (Irene), Maniscalco, A. (Angela), Rossi, A. (Alessandra), Bernard, L. (Loris), Tranchant, M. (Martine), Valois, M.-F. (Marie-France), Turgeon, A. (Annie), Heguy, L. (Lea), Yee, P.S. (Phuah Sze), Kang, P. (Peter), Nee, K.I. (Kang In), Mariapun, S. (Shivaani), Sook-Yee, Y. (Yoon), Lee, D.S.C. (Daphne S.C.), Ching, T.Y. (Teh Yew), Taib, N.A.M. (Nur Aishah Mohd), Otsukka, M. (Meeri), Mononen, K. (Kari), Selander, T. (Teresa), Weerasooriya, N. (Nayana), Krol-Warmerdam, E.M.M. (Elly), Molenaar, J., Blom, J., Szeszenia-Dabrowska, N. (Neonilia), Peplonska, B. (Beata), Zatonski, W. (Witold), Chao, P. (Pei), Stagner, M. (Michael), Bos, P. (Petra), Blom, J. (Jannet), Crepin, E. (Ellen), Nieuwlaat, A. (Anja), Heemskerk, A. (Annette), Higham, S. (Sue), Cramp, H.E. (Helen), Connley, D. (Daniel), Balasubramanian, S. (Sabapathy), Brock, I.W. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Kerbrat, P. (Pierre), Arveux, P. (Patrick), Le Scodan, R. (Romuald), Raoul, Y. (Yves), Laurent-Puig, P. (Pierre), Mulot, C. (Claire), Stegmaier, C. (Christa), Butterbach, K. (Katja), Karstens, J.H. (Johann), Flesch-Janys, D. (Dieter), Seibold, P. (Petra), Vrieling, A. (Alina), Nickels, S. (Stefan), Radice, P. (Paolo), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Kauppila, S. (Saila), Conroy, D. (Don), Baynes, C. (Caroline), Chua, K. (Kimberley), Pilarski, R. (Robert), Guo, X. (Xingyi), Long, J. (Jirong), Zeng, C. (Chenjie), Michailidou, K. (Kyriaki), Ghoussaini, M. (Maya), Bolla, M.K. (Manjeet), Wang, Q. (Qing), Milne, R.L. (Roger L.), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Beesley, J. (Jonathan), Kar, S. (Siddhartha), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, S.E. (Stig), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Broekss, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, H. (Hui), Canisius, S. (Sander), Chang-Claude, J. (Jenny), Choi, J.-Y. (J.), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Droit, A. (Arnaud), Dörk, T. (Thilo), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Gaborieau, V. (Valerie), García-Closas, M. (Montserrat), Giles, G.G. (Graham G.), Grip, M. (Mervi), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hamann, U. (Ute), Hartman, J.M. (Joost), Hollestelle, A. (Antoinette), Hopper, J.L. (John L.), Hsiung, C.-N. (Chia-Ni), Ito, H. (Hidemi), Jakubowska, A. (Anna), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Khan, S. (Sofia), Knight, J.A. (Julia), Kosma, V-M. (Veli-Matti), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lophatananon, A. (Artitaya), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federick), Matsuo, K. (Keitaro), McLean, C.A. (Catriona Ann), Meindl, A. (Alfons), Muir, K. (Kenneth), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Olson, J.E. (Janet), Orr, N. (Nick), Peterlongo, P. (Paolo), Putti, T.C. (Thomas Choudary), Rudolph, A. (Anja), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Shen, C-Y. (Chen-Yang), Shi, J. (Jiajun), Shrubsole, M. (Martha), Southey, M.C. (Melissa), Swerdlow, A.J. (Anthony ), Teo, S.H. (Soo Hwang), Thienpont, B. (Bernard), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-chen), Ouweland, A.M.W. (Ans) van den, Wen, W. (Wanqing), Winqvist, R. (Robert), Wu, A. (Anna), Yip, C.H. (Cheng Har), Zamora, M.P. (Pilar), Zheng, Y. (Ying), Hall, P. (Per), Pharoah, P.D.P. (Paul), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Easton, D.F. (Douglas F.), Zheng, W. (Wei), Eeles, R. (Rosalind), Al Olama, A.A. (Ali Amin), Kote-Jarai, Z., Benlloch, S. (Sara), Antoniou, A.C. (Antonis), McGuffog, L. (Lesley), Offit, K. (Kenneth), Lee, A. (Andrew), Dicks, E. (Ed), Luccarini, C. (Craig), Tessier, D.C. (Daniel C.), Bacot, F. (Francois), Vincent, D. (Daniel), La Boissière, S. (Sylvie), Robidoux, F. (Frederic), Nielsen, S.F. (Sune), Cunningham, J.M. (Julie), Windebank, S.A. (Sharon A.), Hilker, C.A. (Christopher A.), Meyer, J. (Jeffrey), Angelakos, M. (Maggie), Maskiell, J. (Judi), Rutgers, E.J. (Emiel J.), Verhoef, S., Hogervorst, F.B.L. (Frans), Boonyawongviroj, P. (Prat), Siriwanarungsan, P. (Pornthep), Schrauder, A. (André), Rübner, M. (Matthias), Oeser, S. (Sonja), Landrith, S. (Silke), Williams, E. (Eileen), Ryder-Mills, E. (Elaine), Sargus, K. (Kara), McInerney, N. (Niall), Colleran, G. (Gabrielle), Rowan, A. (Andrew), Jones, A. (Angela), Sohn, C. (Christof), Schneeweiß, A. (Andeas), Bugert, P. (Peter), Álvarez, N. (Nuria), Bernstein, L. (Leslie), Lacey, J. (James), Wang, S. (Sophia), Ma, H. (Huiyan), Lu, Y. (Yani), Clague De Hart, J. (Jessica), Deapen, D. (Dennis), Pinder, R. (Rich), Lee, E. (Eunjung), Schumacher, F.R. (Fredrick), Horn-Ross, P. (Pam), Reynolds, P. (Peggy), Nelson, D. (David), Park, H. (Hannah), Ziegler, H. (Hartwig), Wolf, S. (Sonja), Hermann, V. (Volker), Lo, W.-Y. (Wing-Yee), Justenhoven, C. (Christina), Ko, Y.-D. (Yon-Dschun), Baisch, C. (Christian), Fischer, H.-P. (Hans-Peter), Pesch, B. (Beate), Rabstein, S. (Sylvia), Lotz, A. (Anne), Harth, V. (Volker), Heikkinen, T. (Tuomas), Erkkilä, I. (Irja), Aaltonen, K. (Kirsimari), Smitten, K. (Karl) von, Antonenkova, N.N. (Natalia), Hillemanns, P. (Peter), Christiansen, H. (Hans), Myöhänen, E. (Eija), Kemiläinen, H. (Helena), Thorne, H. (Heather), Niedermayr, E. (Eveline), Bowtell, D., De Fazio, A. (Anna), Gertig, D., Green, A., Webb, P. (Penny), Parsons, P., Hayward, N., Webb, P.M. (P.), Whiteman, D., Fung, A. (Annie), Yashiki, J. (June), Peuteman, G. (Gilian), Smeets, D. (Dominiek), Van Brussel, T. (Thomas), Corthouts, K. (Kathleen), Obi, N. (Nadia), Heinz, J. (Judith), Behrens, T.W. (Timothy), Eilber, U. (Ursula), Celik, M. (Muhabbet), Olchers, T. (Til), Peissel, B. (Bernard), Scuvera, G. (Giulietta), Zaffaroni, D. (Daniela), Bonnani, B. (Bernardo), Feroce, I. (Irene), Maniscalco, A. (Angela), Rossi, A. (Alessandra), Bernard, L. (Loris), Tranchant, M. (Martine), Valois, M.-F. (Marie-France), Turgeon, A. (Annie), Heguy, L. (Lea), Yee, P.S. (Phuah Sze), Kang, P. (Peter), Nee, K.I. (Kang In), Mariapun, S. (Shivaani), Sook-Yee, Y. (Yoon), Lee, D.S.C. (Daphne S.C.), Ching, T.Y. (Teh Yew), Taib, N.A.M. (Nur Aishah Mohd), Otsukka, M. (Meeri), Mononen, K. (Kari), Selander, T. (Teresa), Weerasooriya, N. (Nayana), Krol-Warmerdam, E.M.M. (Elly), Molenaar, J., Blom, J., Szeszenia-Dabrowska, N. (Neonilia), Peplonska, B. (Beata), Zatonski, W. (Witold), Chao, P. (Pei), Stagner, M. (Michael), Bos, P. (Petra), Blom, J. (Jannet), Crepin, E. (Ellen), Nieuwlaat, A. (Anja), Heemskerk, A. (Annette), Higham, S. (Sue), Cramp, H.E. (Helen), Connley, D. (Daniel), Balasubramanian, S. (Sabapathy), Brock, I.W. (Ian), Kerin, M. (Michael), Miller, N. (Nicola), Kerbrat, P. (Pierre), Arveux, P. (Patrick), Le Scodan, R. (Romuald), Raoul, Y. (Yves), Laurent-Puig, P. (Pierre), Mulot, C. (Claire), Stegmaier, C. (Christa), Butterbach, K. (Katja), Karstens, J.H. (Johann), Flesch-Janys, D. (Dieter), Seibold, P. (Petra), Vrieling, A. (Alina), Nickels, S. (Stefan), Radice, P. (Paolo), Pykäs, K. (Katri), Jukkola-Vuorinen, A. (Arja), Kauppila, S. (Saila), Conroy, D. (Don), Baynes, C. (Caroline), Chua, K. (Kimberley), and Pilarski, R. (Robert)

Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

Published
2015
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3. Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

Author

Lambrechts, D, Thienpont, B, Thuillier, V, Sagaert, X, Moisse, M, Peuteman, G, Pericay, C, Folprecht, G, Zalcberg, J, Zilocchi, C, Margherini, E, Chiron, M, Van Cutsem, E, Lambrechts, D, Thienpont, B, Thuillier, V, Sagaert, X, Moisse, M, Peuteman, G, Pericay, C, Folprecht, G, Zalcberg, J, Zilocchi, C, Margherini, E, Chiron, M, and Van Cutsem, E

Abstract

BACKGROUND: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC. METHODS: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs). RESULTS: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs. CONCLUSIONS: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

Published
2015

4. Einfluss von genetischen Varianten in der VEGF-Signalkaskade auf die Rate der pathologischen Komplettremission bei Patientinnen nach neoadjuvanter Therapie mit Bevacizumab – Ergebnisse aus der randomisierten GeparQuinto-Studie

Author

Hein, A, primary, Lambrechts, D, additional, Minckwitz, G von, additional, Häberle, L, additional, Eidtmann, H, additional, Tesch, H, additional, Untch, M, additional, Hilfrich, J, additional, Schem, C, additional, Rezai, M, additional, Gerber, B, additional, Costa, S, additional, Blohmer, J, additional, Schwedler, K, additional, Kittel, K, additional, Fehm, T, additional, Kunz, G, additional, Beckmann, M, additional, Ekici, A, additional, Hanusch, C, additional, Huober, J, additional, Liedtke, C, additional, Mau, C, additional, Moisse, M, additional, Müller, V, additional, Nekljudova, V, additional, Peuteman, G, additional, Rack, B, additional, Rübner, M, additional, Van Brussel, T, additional, Wang, L, additional, Weinshilboum, R, additional, Loibl, S, additional, and Fasching, P, additional

Published
2015
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5. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author

Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, J-I, Pilar Zamora, M, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y-D, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, J, Brand, JS, Brenner, H, Dieffenbach, AK, 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, WY, Chan, CW, Marme, F, Yang, R, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, MJ, Kriege, M, van den Ouweland, AMW, Koppert, LB, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Guenel, P, Therese, T, Sanchez, M, Mulot, C, Blot, W, Cai, Q, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Bogdanova, N, Doerk, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, McKay, J, Wang, X, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S, Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, Easton, DF, Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, J-I, Pilar Zamora, M, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y-D, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, J, Brand, JS, Brenner, H, Dieffenbach, AK, 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, WY, Chan, CW, Marme, F, Yang, R, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, MJ, Kriege, M, van den Ouweland, AMW, Koppert, LB, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Guenel, P, Therese, T, Sanchez, M, Mulot, C, Blot, W, Cai, Q, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Bogdanova, N, Doerk, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, McKay, J, Wang, X, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S, Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, and Easton, DF

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 analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-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 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.

Published
2014

6. Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency

Author

Hatse, S., primary, Lambrechts, D., additional, Verstuyf, A., additional, Smeets, A., additional, Brouwers, B., additional, Vandorpe, T., additional, Brouckaert, O., additional, Peuteman, G., additional, Laenen, A., additional, Verlinden, L., additional, Kriebitzsch, C., additional, Dieudonne, A.-S., additional, Paridaens, R., additional, Neven, P., additional, Christiaens, M.-R., additional, Bouillon, R., additional, and Wildiers, H., additional

Published
2012
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7. P5-05-01: Vitamin D Status in Newly Diagnosed Breast Cancer Patients Inversely Correlates with Tumor Size and Moderately Correlates with Outcome.

Author

Hatse, S, primary, Lambrechts, D, additional, Verstuyf, M, additional, Smeets, A, additional, Brouwers, B, additional, Vandorpe, T, additional, Brouckaert, O, additional, Peuteman, G, additional, Laenen, A, additional, Kriebitzsch, C, additional, Dieudonné, A-S, additional, Paridaens, R, additional, Neven, P, additional, Christiaens, M-R, additional, Bouillon, R, additional, and Wildiers, H, additional

Published
2011
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8. Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

Author

Hein A, Lambrechts D, von Minckwitz G, Häberle L, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Dan Costa S, Blohmer JU, Schwedler K, Kittel K, Fehm T, Kunz G, Beckmann MW, Ekici AB, Hanusch C, Huober J, Liedtke C, Mau C, Moisse M, Müller V, Nekljudova V, Peuteman G, Rack B, Rübner M, Van Brussel T, Wang L, Weinshilboum RM, Loibl S, and Fasching PA

Subjects
Adult, Breast Neoplasms blood supply, Breast Neoplasms genetics, Chemotherapy, Adjuvant, Female, Genetic Association Studies, Genotype, Humans, Middle Aged, Neoadjuvant Therapy, Neovascularization, Pathologic prevention & control, Polymorphism, Single Nucleotide, Treatment Outcome, Vascular Endothelial Growth Factor A genetics, Angiogenesis Inhibitors therapeutic use, Bevacizumab therapeutic use, Breast Neoplasms drug therapy, Neovascularization, Pathologic genetics
Abstract

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers., (© 2015 UICC.)

Published
2015
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9. Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

Author

Lambrechts D, Thienpont B, Thuillier V, Sagaert X, Moisse M, Peuteman G, Pericay C, Folprecht G, Zalcberg J, Zilocchi C, Margherini E, Chiron M, and Van Cutsem E

Subjects
Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, Female, Fluorouracil administration & dosage, Fluorouracil therapeutic use, Humans, Leucovorin administration & dosage, Leucovorin therapeutic use, Male, Middle Aged, Mutation, Neoplasm Metastasis, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds therapeutic use, Polymorphism, Single Nucleotide, Receptors, Vascular Endothelial Growth Factor adverse effects, Recombinant Fusion Proteins adverse effects, Survival Analysis, Treatment Outcome, Vascular Endothelial Growth Factor B genetics, Angiogenesis Inhibitors administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Biomarkers, Tumor blood, Colorectal Neoplasms drug therapy, Interleukin-8 blood, Receptors, Vascular Endothelial Growth Factor administration & dosage, Recombinant Fusion Proteins administration & dosage
Abstract

Background: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC., Methods: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs)., Results: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs., Conclusions: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

Published
2015
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10. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Author

Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menéndez-Rodríguez P, Hardisson D, Mendiola M, González-Neira A, Pita G, Alonso MR, Dennis J, Wang Q, Bolla MK, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Ko YD, Brauch H, Hamann U, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Matsuo K, Ito H, Iwata H, Tajima K, Li J, Brand JS, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lambrechts D, Peuteman G, Christiaens MR, Smeets A, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hartman M, Hui M, Yen Lim W, Wan Chan C, Marme F, Yang R, Bugert P, Lindblom A, Margolin S, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Bojesen SE, Nordestgaard BG, Flyger H, Hooning MJ, Kriege M, van den Ouweland AM, Koppert LB, Fletcher O, Johnson N, dos-Santos-Silva I, Peto J, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Cox A, Cross SS, Reed MW, Schmidt MK, Broeks A, Cornelissen S, Braaf L, Kang D, Choi JY, Park SK, Noh DY, Simard J, Dumont M, Goldberg MS, Labrèche F, Fasching PA, Hein A, Ekici AB, Beckmann MW, Radice P, Peterlongo P, Azzollini J, Barile M, Sawyer E, Tomlinson I, Kerin M, Miller N, Hopper JL, Schmidt DF, Makalic E, Southey MC, Hwang Teo S, Har Yip C, Sivanandan K, Tay WT, Shen CY, Hsiung CN, Yu JC, Hou MF, Guénel P, Truong T, Sanchez M, Mulot C, Blot W, Cai Q, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Bogdanova N, Dörk T, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Shu XO, Lu W, Gao YT, Zhang B, Couch FJ, Toland AE, Yannoukakos D, Sangrajrang S, McKay J, Wang X, Olson JE, Vachon C, Purrington K, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Devilee P, Tollenaar RA, Seynaeve C, Czene K, Eriksson M, Humphreys K, Darabi H, Ahmed S, Shah M, Pharoah PD, Hall P, Giles GG, Benítez J, Dunning AM, Chenevix-Trench G, and Easton DF

Subjects
A Kinase Anchor Proteins genetics, Adult, Alleles, Ataxin-7, Case-Control Studies, Cytoskeletal Proteins genetics, Female, Genome-Wide Association Study, Humans, Middle Aged, NIMA-Related Kinases, Nerve Tissue Proteins genetics, Protein Serine-Threonine Kinases genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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 analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-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 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., (© The Author 2014. Published by Oxford University Press.)

Published
2014
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11. Association of CDH11 with non-syndromic ASD.

Author

Crepel A, De Wolf V, Brison N, Ceulemans B, Walleghem D, Peuteman G, Lambrechts D, Steyaert J, Noens I, Devriendt K, and Peeters H

Subjects
Attention Deficit Disorder with Hyperactivity genetics, Case-Control Studies, Chromosome Aberrations, Female, Genotype, Humans, Male, Cadherins genetics, Child Development Disorders, Pervasive genetics, DNA Copy Number Variations genetics, Polymorphism, Single Nucleotide genetics
Abstract

We report a sporadic patient with Autism Spectrum Disorder (ASD), mild intellectual disability and attention deficit hyperactivity disorder (ADHD) with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)ins(4;5)(q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. Since genetic evidence points towards a role for cadherins in ASD, we studied the possible contribution of CDH11 to ASD. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group [P = 0.0049 (Chi-square = 7.90 1 df) and O.R. 3.88 C.I. = 1.403-10.733]. There was no association for C/T versus T/T [P = 0.6772 (Chi-square = 0.17 1 df)] nor was there association at the allelic level [P = 0.4373 (Chi-square = 0.6 1 df)]. In addition to the association of common variants in CDH11 with ASD, we studied the possible contribution of rare variants by sequencing CDH11 in 247 patients, and found three novel variants in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. In conclusion, the data provide evidence for the involvement of CDH11 in ASD which is consistent with the association of other cadherins with ASD and neuropsychiatric diseases., (© 2014 Wiley Periodicals, Inc.)

Published
2014
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12. Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab.

Author

Smith CG, Fisher D, Claes B, Maughan TS, Idziaszczyk S, Peuteman G, Harris R, James MD, Meade A, Jasani B, Adams RA, Kenny S, Kaplan R, Lambrechts D, and Cheadle JP

Subjects
Antibodies, Monoclonal, Humanized administration & dosage, Biomarkers, Tumor genetics, Carcinogenesis genetics, Carcinogenesis pathology, Cetuximab, Class I Phosphatidylinositol 3-Kinases, Clinical Trials as Topic, Colorectal Neoplasms pathology, High-Throughput Nucleotide Sequencing, Humans, Microsatellite Instability, Mutation, Neoplasm Metastasis drug therapy, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras), Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, ErbB Receptors genetics, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins genetics, ras Proteins genetics
Abstract

Purpose: To study the somatic molecular profile of the EGF receptor (EGFR) pathway in advanced colorectal cancer, its relationship to prognosis, the site of the primary and metastases, and response to cetuximab., Experimental Design: We used Sequenom and Pyrosequencing for high-throughput somatic profiling of the EGFR pathway in 1,976 tumors from patients with advanced colorectal cancer from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). Correlations between mutations, clinicopathologic, response, and survival data were carried out., Results: Sequenom and Pyrosequencing had 99.0% (9,961/10,063) genotype concordance. We identified 13 different KRAS mutations in 42.3% of advanced colorectal cancers, 2 BRAF mutations in 9.0%, 4 NRAS mutations in 3.6%, and 5 PIK3CA mutations in 12.7%. 4.2% of advanced colorectal cancers had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations cooccurred (P = 8.9 × 10(-4)) as did MSI and BRAF mutations (P = 5.3 × 10(-10)). KRAS mutations were associated with right colon cancers (P = 5.2 × 10(-5)) and BRAF mutations with right (P = 7.2 × 10(-5)) and transverse colon (P = 9.8 × 10(-6)) cancers. KRAS mutations were associated with lung-only metastases (P = 2.3 × 10(-4)), BRAF mutations with peritoneal (P = 9.2 × 10(-4)) and nodal-only (P = 3.7 × 10(-5)) metastases, and MSI (BRAF(WT)) with nodal-only metastases (P = 2.9 × 10(-4)). MSI (BRAF(WT)) was associated with worse survival (HR = 1.89, 95% CI 1.30-2.76, P = 8.5 × 10(-4)). No mutations, subsets of mutations, or MSI status were associated with response to cetuximab., Conclusions: Our data support a functional cooperation between KRAS and PIK3CA in colorectal tumorigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN., (©2013 AACR.)

Published
2013
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13. Influence of 23 coronary artery disease variants on recurrent myocardial infarction or cardiac death: the GRACE Genetics Study.

Author

Wauters E, Carruthers KF, Buysschaert I, Dunbar DR, Peuteman G, Belmans A, Budaj A, Van de Werf F, Lambrechts D, and Fox KA

Subjects
ABO Blood-Group System genetics, Aged, Belgium epidemiology, Coronary Artery Disease mortality, Death, Sudden, Cardiac epidemiology, Female, Gene Frequency, Genetic Loci genetics, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Myocardial Infarction mortality, Phenotype, Poland epidemiology, Prognosis, Prospective Studies, Recurrence, Registries, Risk Factors, United Kingdom epidemiology, Coronary Artery Disease genetics, Death, Sudden, Cardiac etiology, Genetic Predisposition to Disease genetics, Myocardial Infarction genetics
Abstract

Aims: A pooled analysis of 14 genome-wide association studies revealed 23 susceptibility loci for coronary artery disease (CAD), thereby providing the most comprehensive genetic blueprint of CAD susceptibility. Here, we evaluated whether these 23 loci also predispose to recurrent myocardial infarction (MI) or cardiac death following an acute coronary syndrome (ACS)., Methods and Results: A total of 2099 ACS patients enrolled in the Global Registry of Acute Coronary Events (GRACE) UK-Belgian study were prospectively followed for a median of 5 years (1668 days). C-allele carriers of the rs579459 variant, which is located upstream of the ABO gene and correlates with blood group A, were independently associated with recurrent MI [multivariable-adjusted hazard ratio (HR) 2.25, CI = 1.37-3.71; P = 0.001] and with recurrent MI or cardiac death [multivariable-adjusted (HR) 1.80, CI = 1.09-2.95; P = 0.021] within 5 years after an index ACS. The association of rs579459 was replicated in 1250 Polish patients with 6 months follow-up after an index ACS [multivariable-adjusted (HR) 2.70, CI = 1.26-5.82; P = 0.011 for recurrent MI]. Addition of rs579459 to a prediction model of 17 clinical risk factors improved risk classification for recurrent MI or cardiac death at 6 months as calculated by the integrated discrimination improvement method (P = 0.037), but not by C-statistics (P = 0.096)., Conclusion: In this observational study, rs579459 was independently associated with adverse cardiac outcome after ACS. A weak improvement in clinical risk prediction was also observed, suggesting that rs579459 should be further tested as a potentially relevant contributor to risk prediction models for adverse outcome following ACS.

Published
2013
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14. A variant at chromosome 9p21 is associated with recurrent myocardial infarction and cardiac death after acute coronary syndrome: the GRACE Genetics Study.

Author

Buysschaert I, Carruthers KF, Dunbar DR, Peuteman G, Rietzschel E, Belmans A, Hedley A, De Meyer T, Budaj A, Van de Werf F, Lambrechts D, and Fox KA

Subjects
Aged, Female, Genetic Predisposition to Disease genetics, Genetic Testing, Genotype, Hospitalization, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Prospective Studies, Recurrence, Registries, Risk Factors, Acute Coronary Syndrome genetics, Chromosomes, Human, Pair 9 genetics, Death, Sudden, Cardiac etiology, Genes, p16, Myocardial Infarction genetics
Abstract

Aims: Recent genetic studies identified the rs1333049 variant on chromosome 9p21 as a major susceptibility locus for coronary artery disease and myocardial infarction (MI). Here, we evaluated whether this variant also contributes to recurrent MI or cardiac death following an acute coronary syndrome (ACS)., Methods and Results: A total of 3247 patients with ACS enrolled in the Global Registry of Acute Coronary Events (GRACE) in three distinct populations (UK, Belgium and Poland) were prospectively followed for 6 months and genotyped for rs1333049, in addition to 3004 and 2467 healthy controls from the UK and Belgium. After having confirmed that the at-risk C allele of rs1333049 was associated with index ACS in the UK and Belgian populations, we found that the rs1333049 at-risk C allele was significantly and independently associated with recurrent MI [age- and gender-adjusted hazard ratio (HR) 1.48, CI = 1.00-2.19, P = 0.048; and multivariable-adjusted HR 1.47, CI = 0.99-2.18; P = 0.053] and with recurrent MI or cardiac death (age- and gender-adjusted HR 1.58, CI = 1.00-2.48; P = 0.045; and multivariable adjusted HR 1.49, CI = 1.03-1.98; P = 0.028) within 6 months after an index ACS. Inclusion of rs1333049 into the GRACE risk score significantly improved classification for recurrent MI or cardiac death (P = 0.040), as calculated by the integrated discrimination improvement method., Conclusion: In this large observational study, the 9p21 variant was independently associated with adverse cardiac outcome after ACS.

Published
2010
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