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1. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44–GeparQuinto)

Author

von Minckwitz, G., Loibl, S., Untch, M., Eidtmann, H., Rezai, M., Fasching, P.A., Tesch, H., Eggemann, H., Schrader, I., Kittel, K., Hanusch, C., Huober, J., Solbach, C., Jackisch, C., Kunz, G., Blohmer, J.U., Hauschild, M., Fehm, T., Nekljudova, V., Gerber, B., Gnauert, K., Heinrich, B., Prätz, T., Groh, U., Tanzer, H., Villena, C., Tulusan, A., Liedtke, B., Blohmer, J.-U., Mau, C., Potenberg, J., Schilling, J., Just, M., Weiss, E., Bückner, U., Wolfgarten, M., Lorenz, R., Doering, G., Feidicker, S., Krabisch, P., Deichert, U., Augustin, D., Kast, K., Nestle-Krämling, C., Höß, C., Terhaag, J., Fasching, P., Staib, P., Aktas, B., Kühn, T., Khandan, F., Möbus, V., Stickeler, E., Heinrich, G., Wagner, H., Abdallah, A., Dewitz, T., Emons, G., Belau, A., Rethwisch, V., Lantzsch, T., Thomssen, C., Mattner, U., Nugent, A., Müller, V., Noesselt, T., Holms, F., Müller, T., Deuker, J.-U., Strumberg, D., Uleer, C., Solomayer, E., Runnebaum, I., Link, H., Tomé, O., Ulmer, H.-U., Conrad, B., Feisel-Schwickardi, G., Schumacher, C., Steinmetz, T., Bauerfeind, I., Kremers, S., Langanke, D., Kullmer, U., Ober, A., Fischer, D., Kohls, A., Weikel, W., Bischoff, J., Freese, K., Schmidt, M., Wiest, W., Sütterlin, M., Dietrich, M., Grießhammer, M., Burgmann, D.-M., Rack, B., Salat, C., Sattler, D., Tio, J., von Abel, E., Christensen, B., Burkamp, U., Köhne, C.-H., Meinerz, W., Graßhoff, S.-T., Decker, T., Overkamp, F., Thalmann, I., Sallmann, A., Beck, T., Reimer, T., Bartzke, G., Deryal, M., Weigel, M., Weder, P., Steffens, C.-C., Lemster, S., Stefek, A., Ruhland, F., Hofmann, M., Schuster, J., Simon, W., Kronawitter, U., Clemens, M., Janni, W., Latos, K., Bauer, W., Roßmann, A., Bauer, L., Lampe, D., Heyl, V., Hoffmann, G., Lorenz-Salehi, F., Hackmann, J., and Schlag, R.

Published
2014
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5. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).

Published
2020
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6. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author

Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., Schmutzler R.K., Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., and Schmutzler R.K.

Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2020

8. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Escala-Garcia, M., Guo, Q., Dörk, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M.K., Wang, Q., Abraham, J., Andrulis, I.L., Anton-Culver, H., Arndt, V., Auer, P.L., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S.E., Bonanni, B., Børresen-Dale, A.-L., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I.W., Brucker, S.Y., Burwinkel, B., Caldas, C., Caldés, T., Campa, D., Canzian, F., Carracedo, A., Carter, B.D., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Cheng, T.-Y.D., Chin, S.-F., Clarke, C.L., NBCS Collaborators, Cordina-Duverger, E., Couch, F.J., Cox, D.G., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dunn, J.A., Dunning, A.M., Durcan, L., Dwek, M., Earl, H.M., Ekici, A.B., Eliassen, A.H., Ellberg, C., Engel, C., Eriksson, M., Evans, D.G., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S.M., García-Closas, M., García-Sáenz, J.A., Gaudet, M.M., George, A., Georgoulias, V., Giles, G.G., Glendon, G., Goldgar, D.E., González-Neira, A., Alnæs, G.I.G., Grip, M., Guénel, P., Haeberle, L., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E.F., Harrington, P.A., Hart, S.N., Hartikainen, J.M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M.J., Hoover, R.N., Hopper, J.L., Howell, A., Huang, G., Humphreys, K., Hunter, D.J., Janni, W., John, E.M., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M.J., Khan, S., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Knight, J.A., Ko, Y.-D., Koppert, L.B., Kosma, V.-M., Kraft, P., Kristensen, V.N., Krüger, U., Kühl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindström, S., Linet, M., Lissowska, J., Lo, W.-Y., Loibl, S., Lubiński, J., Lux, M.P., MacInnis, R.J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R.L., Moreno, F., Mulligan, A.M., Mulot, C., Nassir, R., Neuhausen, S.L., Newman, W.T., Nielsen, S.F., Nordestgaard, B.G., Norman, A., Olsson, H., Orr, N., Pankratz, V.S., Park-Simon, T.-W., Perez, J.I.A., Pérez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkäs, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H.S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E.J., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schumacher, F., Schwentner, L., Scott, R.J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M.C., Swerdlow, A.J., Talhouk, A., Tamimi, R.M., Tapper, W.J., Teixeira, M.R., Tengström, M., Terry, M.B., Thöne, K., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H.-U., Untch, M., Vachon, C., van Asperen, C.J., van den Ouweland, A.M.W., van Veen, E.M., Wendt, C., Whittemore, A.S., Willett, W., Winqvist, R., Wolk, A., Yang, X.R., Zhang, Y., Easton, D.F., Fasching, P.A., Nevanlinna, H., Eccles, D.M., Pharoah, P.D.P., and Schmidt, M.K.

Abstract

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P

Published
2019

9. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Escala-Garcia, M. (Maria), Guo, Q. (Qi), Doerk, T. (Thilo), Canisius, S. (Sander), Keeman, R. (Renske), Dennis, J. (Joe), Beesley, J. (Jonathan), Lecarpentier, J. (Julie), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Abraham, J. (Jean), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brentnall, A. (Adam), Brinton, L. (Louise), Broberg, P. (Per), Brock, I. W. (Ian W.), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Caldas, C. (Carlos), Caldes, T. (Trinidad), Campa, D. (Daniele), Canzian, F. (Federico), Carracedo, A. (Angel), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Cheng, T. D. (Ting-Yuan David), Chin, S.-F. (Suet-Feung), Clarke, C. L. (Christine L.), Cordina-Duverger, E. (Emilie), Couch, F. J. (Fergus J.), Cox, D. G. (David G.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dunn, J. A. (Janet A.), Dunning, A. M. (Alison M.), Durcan, L. (Lorraine), Dwek, M. (Miriam), Earl, H. M. (Helena M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Figueroa, J. (Jonine), Flesch-Janys, D. (Dieter), Flyger, H. (Henrik), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Galle, E. (Eva), Gapstur, S. M. (Susan M.), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), George, A. (Angela), Georgoulias, V. (Vassilios), Giles, G. G. (Graham G.), Glendon, G. (Gord), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hankinson, S. (Susan), Harkness, E. F. (Elaine F.), Harrington, P. A. (Patricia A.), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hein, A. (Alexander), Hillemanns, P. (Peter), Hiller, L. (Louise), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jukkola-Vuorinen, A. (Arja), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kabisch, M. (Maria), Kaczmarek, K. (Katarzyna), Kerin, M. J. (Michael J.), Khan, S. (Sofia), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Kitahara, C. M. (Cari M.), Knight, J. A. (Julia A.), Ko, Y.-D. (Yon-Dschun), Koppert, L. B. (Linetta B.), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kuehl, T. (Tabea), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Li, L. (Lian), Lindblom, A. (Annika), Lindstrom, S. (Sara), Linet, M. (Martha), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Lubinski, J. (Jan), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maierthaler, M. (Melanie), Maishman, T. (Tom), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), McLean, C. (Catriona), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, N. (Nicola), Milne, R. L. (Roger L.), Moreno, F. (Fernando), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Nassir, R. (Rami), Neuhausen, S. L. (Susan L.), Newman, W. T. (William T.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Norman, A. (Aaron), Olsson, H. (Hakan), Orr, N. (Nick), Pankratz, V. S. (V. Shane), Park-Simon, T.-W. (Tjoung-Won), Perez, J. I. (Jose I. A.), Perez-Barrios, C. (Clara), Peterlongo, P. (Paolo), Petridis, C. (Christos), Pinchev, M. (Mila), Prajzendanc, K. (Karoliona), Prentice, R. (Ross), Presneau, N. (Nadege), Prokofieva, D. (Darya), Pylkas, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Ramachandran, D. (Dhanya), Rennert, G. (Gadi), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmidt, D. F. (Daniel F.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schumacher, F. (Fredrick), Schwentner, L. (Lukas), Scott, R. J. (Rodney J.), Scott, C. (Christopher), Seynaeve, C. (Caroline), Shah, M. (Mitul), Simard, J. (Jacques), Smeets, A. (Ann), Sohn, C. (Christof), Southey, M. C. (Melissa C.), Swerdlow, A. J. (Anthony J.), Talhouk, A. (Aline), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teixeira, M. R. (Manuel R.), Tengstrom, M. (Maria), Terry, M. B. (Mary Beth), Thoene, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Therese), Turman, C. (Constance), Turnbull, C. (Clare), Ulmer, H.-U. (Hans-Ulrich), Untch, M. (Michael), Vachon, C. (Celine), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Veen, E. M. (Elke M.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Willett, W. (Walter), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zhang, Y. (Yan), Easton, D. F. (Douglas F.), Fasching, P. A. (Peter A.), Nevanlinna, H. (Heli), Eccles, D. M. (Diana M.), Pharoah, P. D. (Paul D. P.), and Schmidt, M. K. (Marjanka K.)

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10−8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10−7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10−7, HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP

Published
2019

10. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author

Garcia-Closas M., Moreno F., Mulligan A.M., Mulot C., Nassir R., Neuhausen S.L., Newman W.T., Nielsen S.F., Nordestgaard B.G., Norman A., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., Petridis C., Pinchev M., Prajzendanc K., Prentice R., Presneau N., Prokofieva D., Pylkas K., Rack B., Radice P., Ramachandran D., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schwentner L., Scott R.J., Scott C., Seynaeve C., Shah M., Simard J., Smeets A., Sohn C., Southey M.C., Swerdlow A.J., Talhouk A., Tamimi R.M., Tapper W.J., Teixeira M.R., Tengstrom M., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Torres D., Truong T., Turman C., Turnbull C., Ulmer H.-U., Untch M., Vachon C., van Asperen C.J., van den Ouweland A.M.W., van Veen E.M., Wendt C., Whittemore A.S., Willett W., Winqvist R., Wolk A., Yang X.R., Zhang Y., Easton D.F., Fasching P.A., Nevanlinna H., Eccles D.M., Pharoah P.D.P., Schmidt M.K., Escala-Garcia M., Guo Q., Dork T., Canisius S., Keeman R., Dennis J., Beesley J., Lecarpentier J., Bolla M.K., Wang Q., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Boeckx B., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Brenner H., Brentnall A., Brinton L., Broberg P., Brock I.W., Brucker S.Y., Burwinkel B., Caldas C., Caldes T., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Cheng T.-Y.D., Chin S.-F., Clarke C.L., Cordina-Duverger E., Couch F.J., Cox D.G., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dunn J.A., Dunning A.M., Durcan L., Dwek M., Earl H.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Figueroa J., Flesch-Janys D., Flyger H., Gabrielson M., Gago-Dominguez M., Galle E., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Georgoulias V., Giles G.G., Glendon G., Goldgar D.E., Gonzalez-Neira A., Alnaes G.I.G., Grip M., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hankinson S., Harkness E.F., Harrington P.A., Hart S.N., Hartikainen J.M., Hein A., Hillemanns P., Hiller L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Janni W., John E.M., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kabisch M., Kaczmarek K., Kerin M.J., Khan S., Khusnutdinova E., Kiiski J.I., Kitahara C.M., Knight J.A., Ko Y.-D., Koppert L.B., Kosma V.-M., Kraft P., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Li L., Lindblom A., Lindstrom S., Linet M., Lissowska J., Lo W.-Y., Loibl S., Lubinski J., Lux M.P., MacInnis R.J., Maierthaler M., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Mavroudis D., McLean C., Meindl A., Middha P., Miller N., Milne R.L., Garcia-Closas M., Moreno F., Mulligan A.M., Mulot C., Nassir R., Neuhausen S.L., Newman W.T., Nielsen S.F., Nordestgaard B.G., Norman A., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., Petridis C., Pinchev M., Prajzendanc K., Prentice R., Presneau N., Prokofieva D., Pylkas K., Rack B., Radice P., Ramachandran D., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schwentner L., Scott R.J., Scott C., Seynaeve C., Shah M., Simard J., Smeets A., Sohn C., Southey M.C., Swerdlow A.J., Talhouk A., Tamimi R.M., Tapper W.J., Teixeira M.R., Tengstrom M., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Torres D., Truong T., Turman C., Turnbull C., Ulmer H.-U., Untch M., Vachon C., van Asperen C.J., van den Ouweland A.M.W., van Veen E.M., Wendt C., Whittemore A.S., Willett W., Winqvist R., Wolk A., Yang X.R., Zhang Y., Easton D.F., Fasching P.A., Nevanlinna H., Eccles D.M., Pharoah P.D.P., Schmidt M.K., Escala-Garcia M., Guo Q., Dork T., Canisius S., Keeman R., Dennis J., Beesley J., Lecarpentier J., Bolla M.K., Wang Q., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Boeckx B., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Brenner H., Brentnall A., Brinton L., Broberg P., Brock I.W., Brucker S.Y., Burwinkel B., Caldas C., Caldes T., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Cheng T.-Y.D., Chin S.-F., Clarke C.L., Cordina-Duverger E., Couch F.J., Cox D.G., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dunn J.A., Dunning A.M., Durcan L., Dwek M., Earl H.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Figueroa J., Flesch-Janys D., Flyger H., Gabrielson M., Gago-Dominguez M., Galle E., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Georgoulias V., Giles G.G., Glendon G., Goldgar D.E., Gonzalez-Neira A., Alnaes G.I.G., Grip M., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hankinson S., Harkness E.F., Harrington P.A., Hart S.N., Hartikainen J.M., Hein A., Hillemanns P., Hiller L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Janni W., John E.M., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kabisch M., Kaczmarek K., Kerin M.J., Khan S., Khusnutdinova E., Kiiski J.I., Kitahara C.M., Knight J.A., Ko Y.-D., Koppert L.B., Kosma V.-M., Kraft P., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Li L., Lindblom A., Lindstrom S., Linet M., Lissowska J., Lo W.-Y., Loibl S., Lubinski J., Lux M.P., MacInnis R.J., Maierthaler M., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Mavroudis D., McLean C., Meindl A., Middha P., Miller N., and Milne R.L.

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Method(s): Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Result(s): We did not find any variant associated with breast cancer-specific mortality at P < 5 x 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 x 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 x 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusion(s): We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.Copyright © 2019, The Author(s).

Published
2019

11. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Author

Giles G.G., Bonanni B., Pinchev M., Plaseska-Karanfilska D., Polley E.C., Prentice R., Presneau N., Prokofyeva D., Purrington K., Pylkas K., Rack B., Radice P., Rau-Murthy R., Rennert G., Rennert H.S., Rhenius V., Robson M., Romero A., Ruddy K.J., Ruebner M., Saloustros E., Sandler D.P., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schurmann P., Schwentner L., Scott C., Scott R.J., Seynaeve C., Shah M., Sherman M.E., Shrubsole M.J., Shu X.-O., Slager S., Smeets A., Sohn C., Soucy P., Southey M.C., Spinelli J.J., Stegmaier C., Stone J., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Truong T., Tzardi M., Ulmer H.-U., Untch M., Vachon C.M., van Veen E.M., Vijai J., Weinberg C.R., Wendt C., Whittemore A.S., Wildiers H., Willett W., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zhang Y., Zheng W., Ziogas A., Dunning A.M., Thompson D.J., Chenevix-Trench G., Chang-Claude J., Schmidt M.K., Hall P., Milne R.L., Pharoah P.D.P., Antoniou A.C., Chatterjee N., Kraft P., Garcia-Closas M., Simard J., Easton D.F., Allen J., Mavaddat N., Michailidou K., Dennis J., Lush M., Fachal L., Lee A., Tyrer J.P., Chen T.-H., Wang Q., Bolla M.K., Yang X., Adank M.A., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Auer P.L., Auvinen P., Barrdahl M., Beane Freeman L.E., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Bogdanova N.V., Bojesen S.E., Borresen-Dale A.-L., Brauch H., Bremer M., Brenner H., Brentnall A., Brock I.W., Brooks-Wilson A., Brucker S.Y., Bruning T., Burwinkel B., Campa D., Carter B.D., Castelao J.E., Chanock S.J., Chlebowski R., Christiansen H., Clarke C.L., Collee J.M., Cordina-Duverger E., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dumont M., Durcan L., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fletcher O., Flyger H., Forsti A., Fritschi L., Gabrielson M., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Gilyazova I.R., Glendon G., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Grenaker Alnaes G.I., Grip M., Gronwald J., Grundy A., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hamann U., Hankinson S.E., Harkness E.F., Hart S.N., He W., Hein A., Heyworth J., Hillemanns P., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Jakimovska M., Jakubowska A., Janni W., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kaczmarek K., Kataja V., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Knight J.A., Ko Y.-D., Kosma V.-M., Koutros S., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Lilyquist J., Lindblom A., Lindstrom S., Lissowska J., Lo W.-Y., Loibl S., Long J., Lubinski J., Lux M.P., MacInnis R.J., Maishman T., Makalic E., Maleva Kostovska I., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., McLean C., Meindl A., Menon U., Middha P., Miller N., Moreno F., Mulligan A.M., Mulot C., Munoz-Garzon V.M., Neuhausen S.L., Nevanlinna H., Neven P., Newman W.G., Nielsen S.F., Nordestgaard B.G., Norman A., Offit K., Olson J.E., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., Peto J., Giles G.G., Bonanni B., Pinchev M., Plaseska-Karanfilska D., Polley E.C., Prentice R., Presneau N., Prokofyeva D., Purrington K., Pylkas K., Rack B., Radice P., Rau-Murthy R., Rennert G., Rennert H.S., Rhenius V., Robson M., Romero A., Ruddy K.J., Ruebner M., Saloustros E., Sandler D.P., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schurmann P., Schwentner L., Scott C., Scott R.J., Seynaeve C., Shah M., Sherman M.E., Shrubsole M.J., Shu X.-O., Slager S., Smeets A., Sohn C., Soucy P., Southey M.C., Spinelli J.J., Stegmaier C., Stone J., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Truong T., Tzardi M., Ulmer H.-U., Untch M., Vachon C.M., van Veen E.M., Vijai J., Weinberg C.R., Wendt C., Whittemore A.S., Wildiers H., Willett W., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zhang Y., Zheng W., Ziogas A., Dunning A.M., Thompson D.J., Chenevix-Trench G., Chang-Claude J., Schmidt M.K., Hall P., Milne R.L., Pharoah P.D.P., Antoniou A.C., Chatterjee N., Kraft P., Garcia-Closas M., Simard J., Easton D.F., Allen J., Mavaddat N., Michailidou K., Dennis J., Lush M., Fachal L., Lee A., Tyrer J.P., Chen T.-H., Wang Q., Bolla M.K., Yang X., Adank M.A., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Auer P.L., Auvinen P., Barrdahl M., Beane Freeman L.E., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Bogdanova N.V., Bojesen S.E., Borresen-Dale A.-L., Brauch H., Bremer M., Brenner H., Brentnall A., Brock I.W., Brooks-Wilson A., Brucker S.Y., Bruning T., Burwinkel B., Campa D., Carter B.D., Castelao J.E., Chanock S.J., Chlebowski R., Christiansen H., Clarke C.L., Collee J.M., Cordina-Duverger E., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dumont M., Durcan L., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fletcher O., Flyger H., Forsti A., Fritschi L., Gabrielson M., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Gilyazova I.R., Glendon G., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Grenaker Alnaes G.I., Grip M., Gronwald J., Grundy A., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hamann U., Hankinson S.E., Harkness E.F., Hart S.N., He W., Hein A., Heyworth J., Hillemanns P., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Jakimovska M., Jakubowska A., Janni W., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kaczmarek K., Kataja V., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Knight J.A., Ko Y.-D., Kosma V.-M., Koutros S., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Lilyquist J., Lindblom A., Lindstrom S., Lissowska J., Lo W.-Y., Loibl S., Long J., Lubinski J., Lux M.P., MacInnis R.J., Maishman T., Makalic E., Maleva Kostovska I., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., McLean C., Meindl A., Menon U., Middha P., Miller N., Moreno F., Mulligan A.M., Mulot C., Munoz-Garzon V.M., Neuhausen S.L., Nevanlinna H., Neven P., Newman W.G., Nielsen S.F., Nordestgaard B.G., Norman A., Offit K., Olson J.E., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., and Peto J.

Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.Copyright © 2018 The Authors

Published
2019

12. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, Schmidt, MK, Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, and Schmidt, MK

Abstract

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Published
2019

13. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Author

Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, Easton, DF, Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, and Easton, DF

Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Published
2019

14. Polygenic risk scores for prediction of breast cancer and breast cancer subtypes

Author

Mavaddat, N. (Nasim), Michailidou, K. (Kyriaki), Dennis, J. (Joe), Lush, M. (Michael), Fachal, L. (Laura), Lee, A. (Andrew), Tyrer, J. P. (Jonathan P.), Chen, T.-H. (Ting-Huei), Wang, Q. (Qin), Bolla, M. K. (Manjeet K.), Yang, X. (Xin), Adank, M. A. (Muriel A.), Ahearn, T. (Thomas), Aittomaki, K. (Kristiina), Allen, J. (Jamie), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Auvinen, P. (Paivi), Barrdahl, M. (Myrto), Freeman, L. E. (Laura E. Beane), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Bremer, M. (Michael), Brenner, H. (Hermann), Brentnall, A. (Adam), Brock, I. W. (Ian W.), Brooks-Wilson, A. (Angela), Brucker, S. Y. (Sara Y.), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Campa, D. (Daniele), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chanock, S. J. (Stephen J.), Chlebowski, R. (Rowan), Christiansen, H. (Hans), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cordina-Duverger, E. (Emilie), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), dos-Santos-Silva, I. (Isabel), Dumont, M. (Martine), Durcan, L. (Lorraine), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foersti, A. (Asta), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Georgoulias, V. (Vassilios), Giles, G. G. (Graham G.), Gilyazova, I. R. (Irina R.), Glendon, G. (Gord), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Gronwald, J. (Jacek), Grundy, A. (Anne), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hamann, U. (Ute), Hankinson, S. E. (Susan E.), Harkness, E. F. (Elaine F.), Hart, S. N. (Steven N.), He, W. (Wei), Hein, A. (Alexander), Heyworth, J. (Jane), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Jakimovska, M. (Milena), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, M. E. (Michael E.), Jukkola-Vuorinen, A. (Arja), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kaczmarek, K. (Katarzyna), Kataja, V. (Vesa), Keeman, R. (Renske), Kerin, M. J. (Michael J.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Knight, J. A. (Julia A.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kuehl, T. (Tabea), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lilyquist, J. (Jenna), Lindblom, A. (Annika), Lindstrom, S. (Sara), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Long, J. (Jirong), Lubinski, J. (Jan), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maishman, T. (Tom), Makalic, E. (Enes), Kostovska, I. M. (Ivana Maleva), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Middha, P. (Pooja), Miller, N. (Nicola), Moreno, F. (Fernando), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Munoz-Garzon, V. M. (Victor M.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Norman, A. (Aaron), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Orr, N. (Nick), Pankratz, V. S. (V. Shane), Park-Simon, T.-W. (Tjoung-Won), Perez, J. I. (Jose I. A.), Perez-Barrios, C. (Clara), Peterlongo, P. (Paolo), Peto, J. (Julian), Pinchev, M. (Mila), Plaseska-Karanfilska, D. (Dijana), Polley, E. C. (Eric C.), Prentice, R. (Ross), Presneau, N. (Nadege), Prokofyeva, D. (Darya), Purrington, K. (Kristen), Pylkäs, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Rau-Murthy, R. (Rohini), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Robson, M. (Mark), Romero, A. (Atocha), Ruddy, K. J. (Kathryn J.), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, D. F. (Daniel F.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schumacher, F. (Fredrick), Schuermann, P. (Peter), Schwentner, L. (Lukas), Scott, C. (Christopher), Scott, R. J. (Rodney J.), Seynaeve, C. (Caroline), Shah, M. (Mitul), Sherman, M. E. (Mark E.), Shrubsole, M. J. (Martha J.), Shu, X.-O. (Xiao-Ou), Slager, S. (Susan), Smeets, A. (Ann), Sohn, C. (Christof), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stegmaier, C. (Christa), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Thoene, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Truong, T. (Therese), Tzardi, M. (Maria), Ulmer, H.-U. (Hans-Ulrich), Untch, M. (Michael), Vachon, C. M. (Celine M.), van Veen, E. M. (Elke M.), Vijai, J. (Joseph), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Wildiers, H. (Hans), Willett, W. (Walter), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zhang, Y. (Yan), Zheng, W. (Wei), Ziogas, A. (Argyrios), Clarke, C. (Christine), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, C. S. (C. Soon), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Scott, R. (Rodney), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), Yip, D. (Desmond), Zeps, N. (Nikolajs), Sexton, A. (Adrienne), Dobrovic, A. (Alex), Christian, A. (Alice), Trainer, A. (Alison), Fellows, A. (Andrew), Shelling, A. (Andrew), De Fazio, A. (Anna), Blackburn, A. (Anneke), Crook, A. (Ashley), Meiser, B. (Bettina), Patterson, B. (Briony), Clarke, C. (Christobel), Saunders, C. (Christobel), Hunt, C. (Clare), Scott, C. (Clare), Amor, D. (David), Ortega, D. G. (David Gallego), Marsh, D. (Deb), Edkins, E. (Edward), Salisbury, E. (Elizabeth), Haan, E. (Eric), Macrea, F. (Finlay), Farshid, G. (Gelareh), Lindeman, G. (Geoff), Trench, G. (Georgia), Mann, G. (Graham), Giles, G. (Graham), Gill, G. (Grantley), Thorne, H. (Heather), Campbell, I. (Ian), Hickie, I. (Ian), Caldon, L. (Liz), Winship, I. (Ingrid), Cui, J. (James), Flanagan, J. (James), Kollias, J. (James), Visvader, J. (Jane), Taylor, J. (Jessica), Burke, J. (Jo), Saunus, J. (Jodi), Forbs, J. (John), Hopper, J. (John), Beesley, J. (Jonathan), Kirk, J. (Judy), French, J. (Juliet), Tucker, K. (Kathy), Wu, K. (Kathy), Phillips, K. (Kelly), Forrest, L. (Laura), Lipton, L. (Lara), Andrews, L. (Leslie), Lobb, L. (Lizz), Walker, L. (Logan), Kentwell, M. (Maira), Spurdle, M. (Mandy), Cummings, M. (Margaret), Gleeson, M. (Margaret), Harris, M. (Marion), Jenkins, M. (Mark), Young, M. A. (Mary Anne), Delatycki, M. (Martin), Wallis, M. (Mathew), Burgess, M. (Matthew), Brown, M. (Melissa), Southey, M. (Melissa), Bogwitz, M. (Michael), Field, M. (Michael), Friedlander, M. (Michael), Gattas, M. (Michael), Saleh, M. (Mona), Aghmesheh, M. (Morteza), Hayward, N. (Nick), Pachter, N. (Nick), Cohen, P. (Paul), Duijf, P. (Pascal), James, P. (Paul), Simpson, P. (Pete), Fong, P. (Peter), Butow, P. (Phyllis), Williams, R. (Rachael), Kefford, R. (Rick), Simard, J. (Jacques), Balleine, R.-M. (Rose-Mary), Dawson, S.-J. (Sarah-Jane), Lok, S. (Sheau), O'connell, S. (Shona), Greening, S. (Sian), Nightingale, S. (Sophie), Edwards, S. (Stacey), Fox, S. (Stephen), McLachlan, S.-A. (Sue-Anne), Lakhani, S. (Sunil), Dudding, T. (Tracy), Antill, Y. (Yoland), Sahlberg, K. K. (Kristine K.), Ottestad, L. (Lars), Karesen, R. (Rolf), Schlichting, E. (Ellen), Holmen, M. M. (Marit Muri), Sauer, T. (Toril), Haakensen, V. (Vilde), Engebraten, O. (Olav), Naume, B. (Bjorn), Fossa, A. (Alexander), Kiserud, C. E. (Cecile E.), Reinertsen, K. V. (Kristin, V), Helland, A. (Aslaug), Riis, M. (Margit), Geisler, J. (Juergen), Dunning, A. M. (Alison M.), Thompson, D. J. (Deborah J.), Chenevix-Trench, G. (Georgia), Chang-Claude, J. (Jenny), Schmidt, M. K. (Marjanka K.), Hall, P. (Per), Milne, R. L. (Roger L.), Pharoah, P. D. (Paul D. P.), Antoniou, A. C. (Antonis C.), Chatterjee, N. (Nilanjan), Kraft, P. (Peter), Garcia-Closas, M. (Montserrat), Easton, D. F. (Douglas F.), Mavaddat, N. (Nasim), Michailidou, K. (Kyriaki), Dennis, J. (Joe), Lush, M. (Michael), Fachal, L. (Laura), Lee, A. (Andrew), Tyrer, J. P. (Jonathan P.), Chen, T.-H. (Ting-Huei), Wang, Q. (Qin), Bolla, M. K. (Manjeet K.), Yang, X. (Xin), Adank, M. A. (Muriel A.), Ahearn, T. (Thomas), Aittomaki, K. (Kristiina), Allen, J. (Jamie), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Auvinen, P. (Paivi), Barrdahl, M. (Myrto), Freeman, L. E. (Laura E. Beane), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Bremer, M. (Michael), Brenner, H. (Hermann), Brentnall, A. (Adam), Brock, I. W. (Ian W.), Brooks-Wilson, A. (Angela), Brucker, S. Y. (Sara Y.), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Campa, D. (Daniele), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chanock, S. J. (Stephen J.), Chlebowski, R. (Rowan), Christiansen, H. (Hans), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cordina-Duverger, E. (Emilie), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), dos-Santos-Silva, I. (Isabel), Dumont, M. (Martine), Durcan, L. (Lorraine), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foersti, A. (Asta), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Georgoulias, V. (Vassilios), Giles, G. G. (Graham G.), Gilyazova, I. R. (Irina R.), Glendon, G. (Gord), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Gronwald, J. (Jacek), Grundy, A. (Anne), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hamann, U. (Ute), Hankinson, S. E. (Susan E.), Harkness, E. F. (Elaine F.), Hart, S. N. (Steven N.), He, W. (Wei), Hein, A. (Alexander), Heyworth, J. (Jane), Hillemanns, P. (Peter), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Jakimovska, M. (Milena), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, M. E. (Michael E.), Jukkola-Vuorinen, A. (Arja), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kaczmarek, K. (Katarzyna), Kataja, V. (Vesa), Keeman, R. (Renske), Kerin, M. J. (Michael J.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Knight, J. A. (Julia A.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kuehl, T. (Tabea), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lilyquist, J. (Jenna), Lindblom, A. (Annika), Lindstrom, S. (Sara), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Long, J. (Jirong), Lubinski, J. (Jan), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maishman, T. (Tom), Makalic, E. (Enes), Kostovska, I. M. (Ivana Maleva), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Middha, P. (Pooja), Miller, N. (Nicola), Moreno, F. (Fernando), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Munoz-Garzon, V. M. (Victor M.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Norman, A. (Aaron), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Orr, N. (Nick), Pankratz, V. S. (V. Shane), Park-Simon, T.-W. (Tjoung-Won), Perez, J. I. (Jose I. A.), Perez-Barrios, C. (Clara), Peterlongo, P. (Paolo), Peto, J. (Julian), Pinchev, M. (Mila), Plaseska-Karanfilska, D. (Dijana), Polley, E. C. (Eric C.), Prentice, R. (Ross), Presneau, N. (Nadege), Prokofyeva, D. (Darya), Purrington, K. (Kristen), Pylkäs, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Rau-Murthy, R. (Rohini), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Robson, M. (Mark), Romero, A. (Atocha), Ruddy, K. J. (Kathryn J.), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, D. F. (Daniel F.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schumacher, F. (Fredrick), Schuermann, P. (Peter), Schwentner, L. (Lukas), Scott, C. (Christopher), Scott, R. J. (Rodney J.), Seynaeve, C. (Caroline), Shah, M. (Mitul), Sherman, M. E. (Mark E.), Shrubsole, M. J. (Martha J.), Shu, X.-O. (Xiao-Ou), Slager, S. (Susan), Smeets, A. (Ann), Sohn, C. (Christof), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stegmaier, C. (Christa), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Thoene, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Truong, T. (Therese), Tzardi, M. (Maria), Ulmer, H.-U. (Hans-Ulrich), Untch, M. (Michael), Vachon, C. M. (Celine M.), van Veen, E. M. (Elke M.), Vijai, J. (Joseph), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Wildiers, H. (Hans), Willett, W. (Walter), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zhang, Y. (Yan), Zheng, W. (Wei), Ziogas, A. (Argyrios), Clarke, C. (Christine), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, C. S. (C. Soon), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Scott, R. (Rodney), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), Yip, D. (Desmond), Zeps, N. (Nikolajs), Sexton, A. (Adrienne), Dobrovic, A. (Alex), Christian, A. (Alice), Trainer, A. (Alison), Fellows, A. (Andrew), Shelling, A. (Andrew), De Fazio, A. (Anna), Blackburn, A. (Anneke), Crook, A. (Ashley), Meiser, B. (Bettina), Patterson, B. (Briony), Clarke, C. (Christobel), Saunders, C. (Christobel), Hunt, C. (Clare), Scott, C. (Clare), Amor, D. (David), Ortega, D. G. (David Gallego), Marsh, D. (Deb), Edkins, E. (Edward), Salisbury, E. (Elizabeth), Haan, E. (Eric), Macrea, F. (Finlay), Farshid, G. (Gelareh), Lindeman, G. (Geoff), Trench, G. (Georgia), Mann, G. (Graham), Giles, G. (Graham), Gill, G. (Grantley), Thorne, H. (Heather), Campbell, I. (Ian), Hickie, I. (Ian), Caldon, L. (Liz), Winship, I. (Ingrid), Cui, J. (James), Flanagan, J. (James), Kollias, J. (James), Visvader, J. (Jane), Taylor, J. (Jessica), Burke, J. (Jo), Saunus, J. (Jodi), Forbs, J. (John), Hopper, J. (John), Beesley, J. (Jonathan), Kirk, J. (Judy), French, J. (Juliet), Tucker, K. (Kathy), Wu, K. (Kathy), Phillips, K. (Kelly), Forrest, L. (Laura), Lipton, L. (Lara), Andrews, L. (Leslie), Lobb, L. (Lizz), Walker, L. (Logan), Kentwell, M. (Maira), Spurdle, M. (Mandy), Cummings, M. (Margaret), Gleeson, M. (Margaret), Harris, M. (Marion), Jenkins, M. (Mark), Young, M. A. (Mary Anne), Delatycki, M. (Martin), Wallis, M. (Mathew), Burgess, M. (Matthew), Brown, M. (Melissa), Southey, M. (Melissa), Bogwitz, M. (Michael), Field, M. (Michael), Friedlander, M. (Michael), Gattas, M. (Michael), Saleh, M. (Mona), Aghmesheh, M. (Morteza), Hayward, N. (Nick), Pachter, N. (Nick), Cohen, P. (Paul), Duijf, P. (Pascal), James, P. (Paul), Simpson, P. (Pete), Fong, P. (Peter), Butow, P. (Phyllis), Williams, R. (Rachael), Kefford, R. (Rick), Simard, J. (Jacques), Balleine, R.-M. (Rose-Mary), Dawson, S.-J. (Sarah-Jane), Lok, S. (Sheau), O'connell, S. (Shona), Greening, S. (Sian), Nightingale, S. (Sophie), Edwards, S. (Stacey), Fox, S. (Stephen), McLachlan, S.-A. (Sue-Anne), Lakhani, S. (Sunil), Dudding, T. (Tracy), Antill, Y. (Yoland), Sahlberg, K. K. (Kristine K.), Ottestad, L. (Lars), Karesen, R. (Rolf), Schlichting, E. (Ellen), Holmen, M. M. (Marit Muri), Sauer, T. (Toril), Haakensen, V. (Vilde), Engebraten, O. (Olav), Naume, B. (Bjorn), Fossa, A. (Alexander), Kiserud, C. E. (Cecile E.), Reinertsen, K. V. (Kristin, V), Helland, A. (Aslaug), Riis, M. (Margit), Geisler, J. (Juergen), Dunning, A. M. (Alison M.), Thompson, D. J. (Deborah J.), Chenevix-Trench, G. (Georgia), Chang-Claude, J. (Jenny), Schmidt, M. K. (Marjanka K.), Hall, P. (Per), Milne, R. L. (Roger L.), Pharoah, P. D. (Paul D. P.), Antoniou, A. C. (Antonis C.), Chatterjee, N. (Nilanjan), Kraft, P. (Peter), Garcia-Closas, M. (Montserrat), and Easton, D. F. (Douglas F.)

Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Published
2019

15. Abstract P2-08-10: Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials

Author

Villegas, SL, primary, Lederer, B, additional, Untch, M, additional, Holms, F, additional, Ulmer, H-U, additional, Diebold, K, additional, Fasching, PA, additional, Weber, K, additional, Schmitt, WD, additional, Tesch, H, additional, Rezai, M, additional, Marmé, F, additional, Sinn, B, additional, Hackmann, J, additional, Schneeweiss, A, additional, Tannapfel, A, additional, Nekljudova, V, additional, Denkert, C, additional, and Loibl, S, additional

Published
2019
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16. Body mass index and breast cancer survival: a Mendelian randomization analysis

Author

Guo, Q, Burgess, S, Turman, C, Bolla, MK, Wang, Q, Lush, M, Abraham, J, Aittomäki, K, Andrulis, IL, Apicella, C, Arndt, V, Barrdahl, M, Benitez, J, Berg, CD, Blomqvist, C, Bojesen, SE, Bonanni, B, Brand, JS, Brenner, H, Broeks, A, Burwinkel, B, Caldas, C, Campa, D, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Darabi, H, Devilee, P, Diver, WR, Dunning, AM, Earl, HM, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flesch-Janys, D, Flyger, H, Gapstur, SM, Gaudet, MM, Giles, GG, Glendon, G, Grip, M, Gronwald, J, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Hankinson, S, Hartikainen, JM, Hein, A, Hiller, L, Hogervorst, FB, Holleczek, B, Hooning, MJ, Hoover, RN, Humphreys, K, Hunter, DJ, Hüsing, A, Jakubowska, A, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kataja, V, Investigators, Kconfab/Aocs, Knight, JA, Koppert, LB, Kosma, V-M, Kristensen, VN, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lindström, S, Lissowska, J, Lubinski, J, Machiela, MJ, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McLean, C, Menéndez, P, Milne, RL, Mulligan, A, Muranen, TA, Nevanlinna, H, Neven, P, Nielsen, SF, Nordestgaard, BG, Olson, JE, Perez, JIA, Peterlongo, P, Phillips, K-A, Poole, CJ, Pylkäs, K, Radice, P, Rahman, N, Rüdiger, T, Rudolph, A, Sawyer, EJ, Schumacher, F, Seibold, P, Seynaeve, C, Shah, M, Smeets, A, Southey, MC, Tollenaar, RAEM, Tomlinson, I, Tsimiklis, H, Ulmer, H-U, Vachon, C, Van Den Ouweland, AMW, Veer, LJ, Wildiers, H, Willett, W, Winqvist, R, Zamora, MP, Chenevix-Trench, G, Dörk, T, Easton, DF, García-Closas, M, Kraft, P, Hopper, JL, Zheng, W, Schmidt, MK, Pharoah, PDP, Medical Oncology, and Surgery

Subjects
Genetic Variation, Breast Neoplasms, Mendelian Randomization Analysis, Body mass index, Breast cancer survival, Epidemiology, Genetics, Mendelian randomization, Polymorphism, Single Nucleotide, Risk Assessment, Survival Analysis, White People, Causality, Europe, RC0254, Meta-Analysis as Topic, Receptors, Estrogen, SDG 3 - Good Health and Well-being, Risk Factors, breast cancer survival, Humans, Female, epidemiology, genetics, Cancer
Abstract

Background There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89–1.13, P = 0.95). Conclusions Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Published
2017

17. Body mass index and breast cancer survival:a Mendelian randomization analysis

Author

Guo, Q. (Qi), Burgess, S. (Stephen), Turman, C. (Constance), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Lush, M. (Michael), Abraham, J. (Jean), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Apicella, C. (Carmel), Arndt, V. (Volker), Barrdahl, M. (Myrto), Benitez, J. (Javier), Berg, C. D. (Christine D.), Blomqvist, C. (Carl), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Brand, J. S. (Judith S.), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldas, C. (Carlos), Campa, D. (Daniele), Canzian, F. (Federico), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chin, S.-F. (Suet-Feung), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Darabi, H. (Hatef), Devilee, P. (Peter), Diver, W. R. (W. Ryan), Dunning, A. M. (Alison M.), Earl, H. M. (Helena M.), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flesch-Janys, D. (Dieter), Flyger, H. (Henrik), Gapstur, S. M. (Susan M.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Grip, M. (Mervi), Gronwald, J. (Jacek), Haeberle, L. (Lothar), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Hankinson, S. (Susan), Hartikainen, J. M. (Jaana M.), Hein, A. (Alexander), Hiller, L. (Louise), Hogervorst, F. B. (Frans B.), Holleczek, B. (Bernd), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Humphreys, K. (Keith), Hunter, D. J. (David J.), Husing, A. (Anika), Jakubowska, A. (Anna), Jukkola-Vuorinen, A. (Arja), Kaaks, R. (Rudolf), Kabisch, M. (Maria), Kataja, V. (Vesa), Knight, J. A. (Julia A.), Koppert, L. B. (Linetta B.), Kosma, V.-M. (Veli-Matti), Kristensen, V. N. (Vessela N.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Li, J. (Jingmei), Lindblom, A. (Annika), Lindstrom, S. (Sara), Lissowska, J. (Jolanta), Lubinski, J. (Jan), Machiela, M. J. (Mitchell J.), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Marme, F. (Federik), Martens, J. W. (John W. M.), McLean, C. (Catriona), Menendez, P. (Primitiva), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olson, J. E. (Janet E.), Perez, J. I. (Jose I. A.), Peterlongo, P. (Paolo), Phillips, K.-A. (Kelly-Anne), Poole, C. J. (Christopher J.), Pylkas, K. (Katri), Radice, P. (Paolo), Rahman, N. (Nazneen), Rudiger, T. (Thomas), Rudolph, A. (Anja), Sawyer, E. J. (Elinor J.), Schumacher, F. (Fredrick), Seibold, P. (Petra), Seynaeve, C. (Caroline), Shah, M. (Mitul), Smeets, A. (Ann), Southey, M. C. (Melissa C.), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Tsimiklis, H. (Helen), Ulmer, H.-U. (Hans-Ulrich), Vachon, C. (Celine), van den Ouweland, A. M. (Ans M. W.), Van't Veer, L. J. (Laura J.), Wildiers, H. (Hans), Willett, W. (Walter), Winqvist, R. (Robert), Zamora, M. P. (M. Pilar), Chenevix-Trench, G. (Georgia), Dork, T. (Thilo), Easton, D. F. (Douglas F.), Garcia-Closas, M. (Montserrat), Kraft, P. (Peter), Hopper, J. L. (John L.), Zheng, W. (Wei), Schmidt, M. K. (Marjanka K.), and Pharoah, P. D. (Paul D. P.)

Subjects
Mendelian randomization, breast cancer survival, body mass index, epidemiology, genetics
Abstract

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89–1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Published
2017

18. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS

Author

Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)

Subjects
skin and connective tissue diseases
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p = 7.1 × 10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p = 6.9 × 10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p = 0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p ≤ 0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p = 0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p = 0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

19. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Author

Lei, J, Rudolph, A, Moysich, KB, Rafiq, S, Behrens, S, Goode, EL, Pharoah, PP, Seibold, P, Fasching, PA, Andrulis, IL, Kristensen, VN, Couch, FJ, Hamann, U, Hooning, MJ, Nevanlinna, H, Eilber, U, Bolla, MK, Dennis, J, Wang, Q, Lindblom, A, Mannermaa, A, Lambrechts, D, Garcia-Closas, M, Hall, P, Chenevix-Trench, G, Shah, M, Luben, R, Haeberle, L, Ekici, AB, Beckmann, MW, Knight, JA, Glendon, G, Tchatchou, S, Alnaes, GIG, Borresen-Dale, A-L, Nord, S, Olson, JE, Hallberg, E, Vachon, C, Torres, D, Ulmer, H-U, Ruediger, T, Jager, A, van Deurzen, CH, Tilanus-Linthorst, MM, Muranen, TA, Aittomaki, K, Blomqvist, C, Margolin, S, Kosma, V-M, Hartikainen, JM, Kataja, V, Hatse, S, Wildiers, H, Smeets, A, Figueroa, J, Chanock, SJ, Lissowska, J, Li, J, Humphreys, K, Phillips, K-A, Linn, S, Cornelissen, S, van den Broek, SAJ, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Shen, C-Y, Teo, SH, Taib, NAM, Yip, CH, Ho, GF, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Dunning, AM, Benitez, J, Czene, K, Sucheston, LE, Maishman, T, Tapper, WJ, Eccles, D, Easton, DF, Schmidt, MK, Chang-Claude, J, Lei, J, Rudolph, A, Moysich, KB, Rafiq, S, Behrens, S, Goode, EL, Pharoah, PP, Seibold, P, Fasching, PA, Andrulis, IL, Kristensen, VN, Couch, FJ, Hamann, U, Hooning, MJ, Nevanlinna, H, Eilber, U, Bolla, MK, Dennis, J, Wang, Q, Lindblom, A, Mannermaa, A, Lambrechts, D, Garcia-Closas, M, Hall, P, Chenevix-Trench, G, Shah, M, Luben, R, Haeberle, L, Ekici, AB, Beckmann, MW, Knight, JA, Glendon, G, Tchatchou, S, Alnaes, GIG, Borresen-Dale, A-L, Nord, S, Olson, JE, Hallberg, E, Vachon, C, Torres, D, Ulmer, H-U, Ruediger, T, Jager, A, van Deurzen, CH, Tilanus-Linthorst, MM, Muranen, TA, Aittomaki, K, Blomqvist, C, Margolin, S, Kosma, V-M, Hartikainen, JM, Kataja, V, Hatse, S, Wildiers, H, Smeets, A, Figueroa, J, Chanock, SJ, Lissowska, J, Li, J, Humphreys, K, Phillips, K-A, Linn, S, Cornelissen, S, van den Broek, SAJ, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Shen, C-Y, Teo, SH, Taib, NAM, Yip, CH, Ho, GF, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Dunning, AM, Benitez, J, Czene, K, Sucheston, LE, Maishman, T, Tapper, WJ, Eccles, D, Easton, DF, Schmidt, MK, and Chang-Claude, J

Abstract

INTRODUCTION: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). METHODS: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. RESULTS: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻⁴) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻⁴), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻⁴). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study o

Published
2015

20. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

Author

Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, Garcia-Closas, M, Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, and Garcia-Closas, M

Abstract

BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

Published
2015

23. Comparison of different approaches for assessment of HER2 expression on protein and mRNA level: prediction of chemotherapy response in the neoadjuvant GeparTrio trial (NCT00544765)

Author

Noske, A., primary, Loibl, S., additional, Darb-Esfahani, S., additional, Roller, M., additional, Kronenwett, R., additional, Müller, B. M., additional, Steffen, J., additional, von Toerne, C., additional, Wirtz, R., additional, Baumann, I., additional, Hoffmann, G., additional, Heinrich, G., additional, Grasshoff, S. T., additional, Ulmer, H. U., additional, Denkert, C., additional, and von Minckwitz, G., additional

Published
2010
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27. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, S. P., Beesley, J., Amin Al Olama, A., Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, Adam Stuart, Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A., Rudolph, A., Gonzalez-Neira, A., Wu, A. H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A. B., Burwinkel, B., Karlan, B. Y., Nordestgaard, B. G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C. L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C. B., Hogdall, C. K., Teerlink, C. C., Kang, D., Tessier, D. C., Schaid, D. J., Stram, D. O., Cramer, Daniel William, Neal, D. E., Eccles, D., Flesch-Janys, D., Edwards, D. R. V., Wokozorczyk, D., Levine, D. A., Yannoukakos, D., Sawyer, E. J., Bandera, E. V., Poole, Elizabeth M., Goode, E. L., Khusnutdinova, E., Hogdall, E., Song, F, Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F. C., Wiklund, F., Giles, G. G., Olsson, H., Wildiers, H., Ulmer, H.-U., Pandha, H., Risch, H. A., Darabi, H., Salvesen, H. B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.-Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J. L., Benitez, J., Doherty, J. A., Permuth, J. B., Chang-Claude, J., Donovan, J. L., Dennis, J., Schildkraut, J. M., Schleutker, J., Hopper, J. L., Kupryjanczyk, J., Park, J. Y., Figueroa, J., Clements, J. A., Knight, J. A., Peto, J., Cunningham, J. M., Pow-Sang, J., Batra, J., Czene, K., Lu, K. H., Herkommer, K., Khaw, K.-T., Matsuo, K., Muir, K., Offitt, K., Chen, K., Moysich, K. B., Aittoma ki, K., Odunsi, K., Kiemeney, L. A., Massuger, L. F. A. G., Fitzgerald, L. M., Cook, L. S., Cannon-Albright, L., Hooning, M. J., Pike, M. C., Bolla, M. K., Luedeke, M., Teixeira, M. R., Goodman, M. T., Schmidt, M. K., Riggan, M., Aly, M., Rossing, M. A., Beckmann, M. W., Moisse, M., Sanderson, M., Southey, M. C., Jones, M., Lush, M., Hildebrandt, M. A. T., Hou, M.-F., Schoemaker, M. J., Garcia-Closas, M., Bogdanova, N., Rahman, N., Le, N. D., Orr, N., Wentzensen, N., Pashayan, N., Peterlongo, P., Guenel, P., Brennan, P., Paulo, P., Webb, P. M., Broberg, P., Fasching, P. A., Devilee, P., Wang, Q., Cai, Q., Li, Q., Kaneva, R., Butzow, R., Kopperud, R. K., Schmutzler, R. K., Stephenson, R. A., MacInnis, R. J., Hoover, R. N., Winqvist, R., Ness, R., Milne, R. L., Travis, R. C., Benlloch, S., Olson, S. H., McDonnell, S. K., Tworoger, Shelley Slate, Maia, S., Berndt, S., Lee, S. C., Teo, S.-H., Thibodeau, S. N., Bojesen, S. E., Gapstur, S. M., Kjaer, S. K., Pejovic, T., Tammela, T. L. J., Do rk, T., Bru ning, T., Wahlfors, T., Key, T. J., Edwards, T. L., Menon, U., Hamann, U., Mitev, V., Kosma, V.-M., Setiawan, V. W., Kristensen, V., Arndt, V., Vogel, W., Zheng, W., Sieh, W., Blot, W. J., Kluzniak, W., Shu, X.-O., Gao, Y.-T., Schumacher, F., Freedman, M. L., Berchuck, A., Dunning, A. M., Simard, J., Haiman, C. A., Spurdle, A., Sellers, T. A., Hunter, David J., Henderson, B. E., Kraft, Peter Elias, Chanock, S. J., Couch, F. J., Hall, P., Gayther, S. A., Easton, D. F., Chenevix-Trench, G., Eeles, R., Pharoah, P. D. P., Lambrechts, D., and undefined, undefined

Subjects
breast cancer, ovarian cancer, prostate cancer, genome-wide association studies, pleiotropy
Abstract

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Other Research Unit

Published
2016
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29. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF

Subjects
ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

30. [Reversible bilateral changes in cerebral proton-spin tomography in eclampsia].

Author

Müller C, Obhof W, Druschky KF, and Ulmer HU

Subjects
Adult, Anticonvulsants therapeutic use, Eclampsia drug therapy, Electroencephalography, Female, Humans, Parity, Pregnancy, Brain pathology, Eclampsia pathology, Magnetic Resonance Imaging methods
Abstract

History and Clinical Findings: Case 1: A 19-year-old primigravida was hospitalised in the 24th week of pregnancy after a series of grand-mal seizures. Investigation showed the classical eclamptic triad of oedema, hypertension and proteinuria. Case 2: 6 days post-partum a 24-year-old primipara developed hypertension and typical clinical prodromata. Subsequently she had a series of sometimes initially focal grand-mal seizures., Treatment and Course: In both cases seizures ceased following pharmacological treatment. The pregnancy in the first case remained intact. Cerebral magnetic resonance imaging (MRI) demonstrated characteristic findings in both cases, in case 1 bilateral disseminated supratentorial foci of oedema without space-occupying features, in case 2 occipital white matter oedema and several supratentorial foci. All changes were completely reversible, in case 1 after 10 days, in case 2 after 16 days., Conclusions: Together with the clinical findings the focal changes on MRI provide a characteristic picture. MRI can thus be an important aid to the diagnosis of eclampsia and will prevent a misinterpretation as focal encephalitis or venous sinus thrombosis.

Published
1996
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31. Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer.

Author

Hamann U, Herbold C, Costa S, Solomayer EF, Kaufmann M, Bastert G, Ulmer HU, Frenzel H, and Komitowski D

Subjects
Alleles, BRCA2 Protein, Chromosome Mapping, Genetic Markers, Humans, Breast Neoplasms genetics, Chromosomes, Human, Pair 13, Genes, Retinoblastoma, Neoplasm Proteins genetics, Transcription Factors genetics
Abstract

Recently, the breast cancer susceptibility gene BRCA2 has been identified in chromosome 13q, a region that also contains the retinoblastoma gene RB1. To elucidate a possible role of BRCA2 and RB1 in sporadic breast tumorigenesis, allelic imbalance (AI) at 13q loci was examined in 78 primary sporadic breast tumors. AI was found in 52-63% of tumors. Nine tumors showed AI only in the BRCA2 region but not at RB1. Six tumors showed AI at RB1 but not in the BRCA2 region. AI in the BRCA2 region correlated significantly with aneuploidy (P = 0.032) and AI at RB1 with small tumor size (P = 0.025). Our data suggest that BRCA2 and RB1 may be both distinct target loci for AI on chromosome 13 in sporadic breast cancer.

Published
1996

32. [Pregnancy following organ transplantation].

Author

Kraemer-Hansen H, Goepel E, Ulmer HU, Bitzan M, Press C, Kopp A, Henne-Bruns D, and Kremer B

Subjects
Adult, Female, Fetal Growth Retardation etiology, Graft Rejection drug effects, Graft Rejection physiology, Humans, Immunosuppressive Agents administration & dosage, Infant, Newborn, Kidney Function Tests, Obstetric Labor, Premature etiology, Pregnancy, Abnormalities, Drug-Induced etiology, Immunosuppressive Agents adverse effects, Kidney Transplantation physiology, Postoperative Complications etiology, Pregnancy Complications etiology
Abstract

In 17 of 74 patients, in the 20-40 years of age group, who had undergone an organ transplantation (kidney or liver), the course and outcome of pregnancy were evaluated. In three cases, the pregnancies ended in premature miscarriage and in five cases they were terminated for medical reasons. Nine infants were born alive between the 32nd to the 40th week of gestation, six of them spontaneously, three of them by abdominal Caesarean section. One of these infants born in the 32nd week of gestation with a birth weight of 800 grams died on the second day after birth. One infant born in the 33rd week of gestation showed incidence of a persistent ductus arteriosis Botalli. Four of the nine newborns suffered from intrauterine dystrophy. The birth weight of four further infants corresponded to the 10th to 25th percentile. Neither the incidence of a maternal varicella zoster infection in the early stages of pregnancy nor the reactivation of a herpes simplex (HSV) and cytomegalia virus infection during the pregnancy resulted in any perceptible damage to the infant or transplant. During pregnancy, three of the mothers were treated with immunosuppressants, either with a combination of azathioprine and prednisone (conventional) or cyclosporine (CSA) and prednisone, or with a combination of all three drugs (triple therapy). As opposed to the newborn of those mothers, who had been treated conventionally, the newborn of those treated with CSA showed post partum a tendency towards hypocalcaemia. Two of the mothers gave birth to their infants outside the Federal Republic of Germany.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1990
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33. High-risk pregnancies and amniotic fluid isoamylase activity.

Author

Goepel E, Ulmer HU, and Schlotfeldt TC

Subjects
Female, Humans, Pregnancy, Amniotic Fluid enzymology, Clinical Enzyme Tests, Fetal Diseases diagnosis, Glycoside Hydrolases analysis, Isoamylase analysis, Pregnancy Complications diagnosis
Abstract

A kinetic test (Phadebas) was employed to determine the isoamylase activity in 77 amniotic fluid samples taken from a total of 60 high-risk pregnancies at different gestational ages. It was ascertained that in high-risk pregnancies the s-type isoamylase level frequently deviates from the common scatter range of the respective week of gestation. The measured activity of the s-type isoamylase is subsequently set in relation to the pre- and postnatal state of the newborn. The findings support the assumption that in addition to ultrasound, hormone determination and cardiotocography, the estimation of s-type amylase activity in amniotic fluid may serve as an index for fetal well-being. A reduced secretion of the parotid gland as a result of fetal stress is discussed as a possible cause of the ascertained enzymatic changes in the amniotic fluid.

Published
1990
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34. [Comparison of microwave and infrared thermography in detecting malignant breast tumors].

Author

Ulmer HU, Würthner K, and Lüdecke KM

Subjects
Evaluation Studies as Topic, Female, Humans, Mammography, Microcomputers, Thermography instrumentation, Breast Neoplasms diagnosis, Carcinoma diagnosis, Infrared Rays, Microwaves, Thermography methods
Abstract

Microwave thermography is a new method in the diagnosis of breast cancer. The paper reports on the use of a microwave thermographic unit in the examination of 190 patients. Evaluation criteria are defined and the results are compared with those obtained by infrared thermography.

Published
1984
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35. [The value of thermography in the diagnosis of breast cancer and in the selection of risk groups].

Author

Ulmer HU

Subjects
Adult, Breast Neoplasms genetics, Female, Humans, Middle Aged, Risk Factors, Breast Neoplasms diagnosis, Precancerous Conditions diagnosis, Thermography
Abstract

Within the framework of a prospective screening study for breast cancer, mammographic and thermographic examinations were performed in 11546 clinically asymptomatic women between 1973 and 1980. Until 1986, breast cancer was diagnosed in 141 women. Conforming with the literatur we demonstrate that the accuracy of thermography declines with decreasing tumour size (pTis 27%, pT1 33.3%, pT2 64%). The rate of breast cancer incidence in women with at least one thermogram considered suspicious or requiring further investigation was 2.7 +/- 0.4 during a period of up to 12 years. This value is not higher than that of many other risk factors and lies clearly below the factor of familial predisposition.

Published
1988
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36. Amniotic fluid isoamylase activity in uneventful pregnancies.

Author

Goepel E, Ulmer HU, Pahnke VG, Schlotfeldt TC, and Bode F

Subjects
Female, Gestational Age, Humans, Isoamylase blood, Pancreas enzymology, Pregnancy, Amniotic Fluid enzymology, Glycoside Hydrolases analysis, Isoamylase analysis
Abstract

A kinetic test (Phadebas) was used to determine the isoamylase activity in 50 serum specimens and 159 samples of amniotic fluid. A highly significant difference between the isoamylase patterns of serum and amniotic fluid was ascertained which strongly supports the view that amylase activity in amniotic fluid is not of maternal origin. During the whole course of gestation the activity of pancreatic isoamylase was constantly low whereas there was an increase of nonpancreatic activity (S-type amylase) from 44 +/- 10 U/l in the 18th week of gestation to 445 +/- 170 U/l in week 39/40. A comparison between the dispersion of the ascertained values and the lecithin-sphingomyelin (L/S) ratio showed a clear overlapping. There was a correlation coefficient of r = 0.645 for 115 amniotic fluid specimens examined in our investigation. The findings show that the estimation of nonpancreatic isoamylase (S-type amylase) activity in amniotic fluid is a valuable indirect parameter for determining fetal maturity and fetal lung maturity. The easy and quick determination method will provide even those hospitals with an index of fetal maturity which are presently not in a position to estimate the L/S ratio, thus being of great assistance in the field of premature deliveries.

Published
1989
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38. Intracavitary therapy with radioactive yttrium: results of animal experiments.

Author

Ulmer HU

Subjects
Animals, Guinea Pigs, Injections, Intraperitoneal, Peritoneum radiation effects, Radiation Dosage, Brachytherapy methods, Peritoneal Neoplasms radiotherapy, Yttrium Radioisotopes administration & dosage
Abstract

The distribution of radioactive yttrium was studied in guinea-pigs. The injection of 1,5 mci of radioactive yttrium leads to a mean surface dose of 20 Gy which can be obtained within 5 days. An extrapolation of these findings to the peritoneal surface of human beings should lead to a corresponding dose of 64 mci.

Published
1989

39. Anemia, ferritin and preterm labor.

Author

Ulmer HU and Goepel E

Subjects
Anemia, Hypochromic diagnosis, Erythrocyte Indices, Female, Humans, Obstetric Labor, Premature etiology, Pregnancy, Prospective Studies, Random Allocation, Retrospective Studies, Anemia, Hypochromic blood, Ferritins blood, Hemoglobins analysis, Obstetric Labor, Premature blood, Pregnancy Complications, Hematologic blood
Abstract

The results of this study suggest that the additional determination of serum ferritin in pregnancy is necessary for a more reliable classification of iron deficiency. In 300 pregnant women the hematological values (Hb, MCH and serum ferritin) were determined toward the end of gestation. In 36 per cent of the women both Hb values greater than 11 g/dl and MCH values less than 28 pg fail to give evidence of an existing iron deficiency, indicated by serum ferritin values below 20 micrograms/l. The determination of serum ferritin is of particular relevance as a significant correlation was ascertained between low serum ferritin levels and the incidence of preterm labor: 52.3% of the women with serum ferritin levels below 10 micrograms/l and only 9.5% of the women with serum ferritin levels above 20 micrograms/l went into preterm labor. A convincing explanation for this has not yet been found.

Published
1988
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40. Treatment of advanced cancers of the cervix uteri with external irradiation alone.

Author

Ulmer HU and Frischbier HJ

Subjects
Adult, Aged, Carcinoma, Squamous Cell radiotherapy, Female, Humans, Middle Aged, Radiotherapy adverse effects, Uterine Cervical Neoplasms mortality, Uterine Cervical Neoplasms radiotherapy
Abstract

The five year survival rates of 150 patients who were treated by external irradiation alone for cancers of the cervix uteri are presented. Intracavitary radium therapy had been rejected as inappropriate in all of them on account of the size and type of spread of the tumor. The average age of the selected patients was considerably higher than that of control groups. Results and incidence of side-effects are comparable with those obtained by radium-telecobalt therapy; however, rectovaginal/vesicovaginal fistulas as a reaction to radiation treatment did not occur.

Published
1983
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41. Premature labor contractions and the value of serum ferritin during pregnancy.

Author

Goepel E, Ulmer HU, and Neth RD

Subjects
Anemia, Hypochromic complications, Anemia, Hypochromic diagnosis, Female, Humans, Obstetric Labor, Premature etiology, Predictive Value of Tests, Pregnancy, Pregnancy Complications, Hematologic diagnosis, Pregnancy Trimester, Third, Retrospective Studies, Uterine Contraction, Anemia, Hypochromic blood, Ferritins blood, Obstetric Labor, Premature blood, Pregnancy Complications, Hematologic blood
Abstract

In general, the diagnosis of pregnancy-related anemia relies on the estimation of the hemoglobin level. The findings of this study suggest that the additional estimation of serum ferritin - a reliable index of the iron stores - can improve the diagnosis of anemia. Hematological data of 150 pregnant women were retrospectively related to the courses of pregnancy, in particular to the incidence of premature labor contractions. 70% of the pregnant women included in the investigation had a serum ferritin value below 20 micrograms/l and thus iron deficiency. If the hemoglobin value alone had been estimated, 50.6% of the women with iron deficiency (serum ferritin less than 20 micrograms/l) would not have been detected among those pregnant women with a hemoglobin value of more than 11 g/dl. These findings are also of particular relevance as a significant correlation has been found between the incidence of premature labor contractions and the serum ferritin level: only 11% of the pregnant women investigated whose serum ferritin values exceeded 20 micrograms/l had premature labor contractions, whereas premature labor was recorded in 48% of the pregnant women with serum ferritin values below 10 micrograms/l.

Published
1988
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