Florey Department of Neuroscience and Mental Health - Research Publications

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    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)
    BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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    Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
    Zhan, H ; Ahearn, TU ; Lecarpentier, J ; Barnes, D ; Beesley, J ; Qi, G ; Jiang, X ; O'Mara, TA ; Zhao, N ; Bolla, MK ; Dunning, AM ; Dennis, J ; Wang, Q ; Abu Ful, Z ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auer, PL ; Azzollini, J ; Barrowdale, D ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, A ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bonanni, B ; Bondavalli, D ; Borg, A ; Brauch, H ; Brenner, H ; Briceno, I ; Broeks, A ; Brucker, SY ; Bruening, T ; Burwinkel, B ; Buys, SS ; Byers, H ; Caldes, T ; Caligo, MA ; Calvello, M ; Campa, D ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiaens, M ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Diez, O ; Domchek, SM ; Doerk, T ; Dwek, M ; Eccles, DM ; Ekici, AB ; Evans, DG ; Fasching, PA ; Figueroa, J ; Foretova, L ; Fostira, F ; Friedman, E ; Frost, D ; Gago-Dominguez, M ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Gayther, SA ; Giles, GG ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haeberle, L ; Hahnen, E ; Haiman, CA ; Hake, CR ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Hillemanns, P ; Hogervorst, FBL ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Huebner, H ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Janni, W ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Khan, S ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Konstantopoulou, I ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Laenkholm, A-V ; Lambrechts, D ; Larsson, SC ; Laurent-Puig, P ; Lazaro, C ; Lazarova, E ; Lejbkowicz, F ; Leslie, G ; Lesueur, F ; Lindblom, A ; Lissowska, J ; Lo, W-Y ; Loud, JT ; Lubinski, J ; Lukomska, A ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matricardi, L ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Mingazheva, E ; Montagna, M ; Mulligan, AM ; Mulot, C ; Muranen, TA ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Newman, WG ; Nielsens, FC ; Nikitina-Zake, L ; Nodora, J ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Papi, L ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Peissel, B ; Peixoto, A ; Peshkin, B ; Peterlongo, P ; Peto, J ; Phillips, K-A ; Piedmonte, M ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Prokofyeva, D ; Rack, B ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rennert, G ; Rennert, HS ; Risch, HA ; Romero, A ; Rookus, MA ; Ruebner, M ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Scheuner, MT ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Senter, L ; Sharma, P ; Sherman, ME ; Shu, X-O ; Singer, CF ; Smichkoska, S ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Stone, J ; Stoppa-Lyonnet, D ; Swerdlow, AJ ; Szabo, C ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, M ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Troester, MA ; Truong, T ; Tung, N ; Untch, M ; Vachon, CM ; van den Ouweland, AMW ; van der Kolk, LE ; van Veen, EM ; vanRensburg, EJ ; Vega, A ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wildiers, H ; Winqvist, R ; Wolk, A ; Yang, XR ; Yannoukakos, D ; Zheng, W ; Zorn, KK ; Milne, RL ; Kraft, P ; Simard, J ; Pharoah, PDP ; Michailidou, K ; Antoniou, AC ; Schmidt, MK ; Chenevix-Trench, G ; Easton, DF ; Chatterjee, N ; Garcia-Closas, M (NATURE RESEARCH, 2020-06)
    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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    Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
    Fachal, L ; Aschard, H ; Beesley, J ; Barnes, DR ; Allen, J ; Kar, S ; Pooley, KA ; Dennis, J ; Michailidou, K ; Turman, C ; Soucy, P ; Lemacon, A ; Lush, M ; Tyrer, JP ; Ghoussaini, M ; Marjaneh, MM ; Jiang, X ; Agata, S ; Aittomaki, K ; Rosario Alonso, M ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auber, B ; Auer, PL ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, AM ; Blomqvist, C ; Blot, W ; Bogdanova, N ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borg, A ; Bosse, K ; Brauch, H ; Brenner, H ; Briceno, I ; Brock, IW ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Cai, Q ; Caldes, T ; Caligo, MA ; Camp, NJ ; Campbell, I ; Canzian, F ; Carroll, JS ; Carter, BD ; Castelao, JE ; Chiquette, J ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Collee, JM ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; Devilee, P ; Diez, O ; Ding, YC ; Dite, GS ; Domchek, SM ; Doerk, T ; dos-Santos-Silva, I ; Droit, A ; Dubois, S ; Dumont, M ; Duran, M ; Durcan, L ; Dwek, M ; Eccles, DM ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fletcher, O ; Floris, G ; Flyger, H ; Foretova, L ; Foulkes, WD ; Friedman, E ; Fritschi, L ; Frost, D ; Gabrielson, M ; Gago-Dominguez, M ; Gambino, G ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Georgoulias, V ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Tibiletti, MG ; Greene, MH ; Grip, M ; Gronwald, J ; Grundy, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hartman, M ; He, W ; Healey, CS ; Heemskerk-Gerritsen, BAM ; Heyworth, J ; Hillemanns, P ; Hogervorst, FBL ; Hollestelle, A ; Hooning, MJ ; Hopper, JL ; Howell, A ; Huang, G ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Iwasaki, M ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, PA ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Jones, ME ; Jukkola-Vuorinen, A ; Jung, A ; Kaaks, R ; Kang, D ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Kerin, MJ ; Khusnutdinova, E ; Kiiski, J ; Kirk, J ; Kitahara, CM ; 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, JT ; Lubinski, J ; MacInnis, RJ ; Maishman, T ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matsuo, K ; Maurer, T ; Mavroudis, D ; Mayes, R ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Miller, A ; Miller, N ; Montagna, M ; Moreno, F ; Muir, K ; Mulligan, AM ; Munoz-Garzon, VM ; Muranen, TA ; Narod, SA ; Nassir, R ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Nielsen, FC ; Nikitina-Zake, L ; Norman, A ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Osorio, A ; Pankratz, VS ; Papp, J ; Park, SK ; Park-Simon, T-W ; Parsons, MT ; Paul, J ; Pedersen, IS ; Peissel, B ; Peshkin, B ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Presneau, N ; Prokofyeva, D ; Angel Pujana, M ; Pylkas, K ; Radice, P ; Ramus, SJ ; Rantala, J ; Rau-Murthy, R ; Rennert, G ; Risch, HA ; Robson, M ; Romero, A ; Rossing, M ; Saloustros, E ; Sanchez-Herrero, E ; Sandler, DP ; Santamarina, M ; Saunders, C ; Sawyer, EJ ; Scheuner, MT ; Schmidt, DF ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Scott, C ; Scott, RJ ; Senter, L ; Seynaeve, CM ; Shah, M ; Sharma, P ; Shen, C-Y ; Shu, X-O ; Singer, CF ; Slavin, TP ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Stoppa-Lyonnet, D ; Sutter, C ; Swerdlow, AJ ; Tamimi, RM ; Tan, YY ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Tengstroem, M ; Teo, SH ; Terry, MB ; Teul, A ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Torres-Mejia, G ; Troester, MA ; Truong, T ; Tung, N ; Tzardi, M ; Ulmer, H-U ; Vachon, CM ; van Asperen, CJ ; van der Kolk, LE ; van Rensburg, EJ ; Vega, A ; Viel, A ; Vijai, J ; Vogel, MJ ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Wu, AH ; Yannoukakos, D ; Zhang, Y ; Zheng, W ; Hunter, D ; Pharoah, PDP ; Chang-Claude, J ; Garcia-Closas, M ; Schmidt, MK ; Milne, RL ; Kristensen, VN ; French, JD ; Edwards, SL ; Antoniou, AC ; Chenevix-Trench, G ; Simard, J ; Easton, DF ; Kraft, P ; Dunning, AM ; 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, DM ; 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, FP ; Bronner, M ; Sokolowska, J ; Coulet, F ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Fert-Ferrer, S ; Jiao, Y ; Lesueur, FL ; Barouk-Simonet, E ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Toulas, C ; Reimineras, A ; Sobol, H ; Bressac-de Paillerets, B ; Cabaret, O ; Caron, O ; Guillaud-Bataille, M ; Rouleau, E ; Belotti, M ; Buecher, B ; Caputo, S ; Colas, C ; De Pauw, A ; 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 ; Rogers, MT ; Porteous, ME ; Ahmed, M ; Morrison, PJ ; Brennan, P ; Eeles, R ; Davidson, R ; Sexton, A ; Christian, A ; Trainer, A ; Spigelman, A ; Fellows, A ; Shelling, A ; De Fazio, A ; Blackburn, A ; Crook, A ; Meiser, B ; Patterson, B ; Clarke, C ; Hunt, C ; Scott, C ; Amor, D ; Marsh, D ; Edkins, E ; Salisbury, E ; Haan, E ; Neidermayr, E ; Macrea, F ; Farshid, G ; Lindeman, G ; Trench, G ; Mann, G ; Giles, G ; Gill, G ; Thorne, H ; Hickie, I ; Winship, I ; Flanagan, J ; Kollias, J ; Visvader, J ; Taylor, J ; Burke, J ; Saunus, J ; Forbes, J ; Hopper, J ; French, J ; Tucker, K ; Wu, K ; Phillips, K ; 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 ; 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 ; Balleine, R ; Dawson, S ; 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 ; Hooning, M ; 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, EG ; 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 ; Marsh, D ; Baxter, R ; Yip, D ; Carpenter, J ; Davis, A ; Pathmanathan, N ; Simpson, P ; Graham, D ; Sachchithananthan, M (NATURE RESEARCH, 2020-01-07)
    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.
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    Genome-wide association study of germline variants and breast cancer-specific mortality
    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 (NATURE PUBLISHING GROUP, 2019-03-19)
    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.
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    Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
    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 ; Clarke, C ; Saunders, C ; Hunt, C ; Scott, C ; Amor, D ; Ortega, DG ; Marsh, D ; 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 ; Simpson, 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 (CELL PRESS, 2019-01-03)
    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.