Browsing by Subject "FUNCTIONAL VARIANTS"

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  • Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; KConFab Consortium; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eital; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J.; Novakovic, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F.; Pharoah, Paul; Dunning, Alison M.; Bishop, D. Timothy; Neuhausen, Susan L.; Steele, Linda; Ashworth, Alan; Garcia Closas, Montserrat; Houlston, Richard; Swerdlow, Anthony; Orr, Nick (2021)
    Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 x 10(-06). Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 x 10(-08)). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10(-30)). Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
  • Darabi, Hatef; Beesley, Jonathan; Droit, Arnaud; Kar, Siddhartha; Nord, Silje; Marjaneh, Mahdi Moradi; Soucy, Penny; Michailidou, Kyriaki; Ghoussaini, Maya; Wahl, Hanna Fues; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Alonso, M. Rosario; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Bruening, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Choi, Ji-Yeob; Conroy, Don M.; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Devilee, Peter; Doerk, Thilo; Easton, Douglas F.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; Garcia-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; Gonzalez-Neira, Anna; Guenel, Pascal; Haiman, Christopher A.; Hallberg, Emily; Hamann, Ute; Hartman, Mikael; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Kang, Daehee; Khan, Sofia; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Lambrechts, Diether; Le Marchand, Loic; Lee, Soo Chin; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Mayes, Rebecca; Mckay, James; Meindl, Alfons; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olswold, Curtis; Orr, Nick; Peterlongo, Paolo; Pita, Guillermo; Pylkaes, Katri; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Southey, Melissa C.; Stram, Daniel O.; Surowy, Harald; Swerdlow, Anthony; Teo, Soo H.; Tessier, Daniel C.; Tomlinson, Ian; Torres, Diana; Truong, Therese; Vachon, Celine M.; Vincent, Daniel; Winqvist, Robert; Wu, Anna H.; Wu, Pei-Ei; Yip, Cheng Har; Zheng, Wei; Pharoah, Paul D. P.; Hall, Per; Edwards, Stacey L.; Simard, Jacques; French, Juliet D.; Chenevix-Trench, Georgia; Dunning, Alison M. (2016)
    Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 x 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 x 10-09, r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 x 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
  • Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Hogervorst, Frans B.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Perez, Jose Ignacio Arias; Menendez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Nevanlinna, Heli; Aittomaki, Kristiina; Blomqvist, Carl; Khan, Sofia; GENICA Network; kConFab Investigators; Australian Ovarian Canc Study Grp (2015)
    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
  • 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.; Giles, G.; Gill, G.; Thorne, H.; Campbell, I.; Hickie, I.; Winship, I.; Flanagan, J.; Kollias, J.; Visvader, J.; Stone, J.; Taylor, J.; Burke, J.; Saunus, J.; Forbes, J.; Hopper, J.; Beesley, J.; Kirk, 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, 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.; Collée, M.; van Deurzen, C.; Hooning, M.; Obdeijn, I.-M.; van den Ouweland, A.; Seynaeve, C.; Siesling, S.; Verloop, J.; van Asperen, C.J.; Devilee, P.; 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.; Clarke, C.; Marsh, D.; Scott, R.; Baxter, R.; Yip, D.; Carpenter, J.; Davis, A.; Pathmanathan, N.; Simpson, P.; 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.; 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.; 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.; Mebirouk, N.; 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.; Saunders, C.; Sawyer, E.J.; Scheuner, M.T.; Schmidt, D.F.; Schmutzler, R.K.; Schneeweiss, A.; Schoemaker, M.J.; Schöttker, B.; Schürmann, P.; Scott, C.; 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.; Stone, J.; Stoppa-Lyonnet, D.; 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.; Tischkowitz, M.; 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 Asperen, C.J.; 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.; Milne, R.L.; Kristensen, V.N.; French, J.D.; Edwards, S.L.; Antoniou, A.C.; Chenevix-Trench, G.; Simard, J.; Easton, D.F.; Kraft, P.; Dunning, A.M.; Collaborators, GEMO Study; Collaborators, EMBRACE; Investigators, KConFab; Investigators, HEBON; Investigators, ABCTB (2020)
    Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions. 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.
  • Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; van der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D. P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guenel, Pascal; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; GENICA Network; KConFab Investigators; Norwegian Breast Canc Study (2015)
  • Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura; Lee, Andrew; Tyrer, Jonathan P.; Chen, Ting-Huei; Wang, Qin; Bolla, Manjeet K.; Yang, Xin; Adank, Muriel A.; Ahearn, Thomas; Aittomäki, Kristiina; Allen, Jamie; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Auvinen, Päivi; Barrdahl, Myrto; Beane Freeman, Laura E.; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Bremer, Michael; Brenner, Hermann; Brentnall, Adam; Brock, Ian W.; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Campa, Daniele; Carter, Brian D.; Castelao, Jose E.; Chanock, Stephen J.; Chlebowski, Rowan; Christiansen, Hans; Clarke, Christine L.; Collée, J. Margriet; Cordina-Duverger, Emilie; Cornelissen, Sten; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Försti, Asta; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Georgoulias, Vassilios; Giles, Graham G.; Gilyazova, Irina R.; Glendon, Gord; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Grenaker Alnæs, Grethe I.; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hankinson, Susan E.; Harkness, Elaine F.; Hart, Steven N.; He, Wei; Hein, Alexander; Heyworth, Jane; Hillemanns, Peter; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Jakimovska, Milena; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Michael E.; Jukkola-Vuorinen, Arja; Jung, Audrey; Kaaks, Rudolf; Kaczmarek, Katarzyna; Kataja, Vesa; Keeman, Renske; Kerin, Michael J.; Khusnutdinova, Elza; Kiiski, Johanna I.; Knight, Julia A.; Ko, Yon-Dschun; Kosma, Veli-Matti; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kühl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Lilyquist, Jenna; Lindblom, Annika; Lindström, Sara; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lubiński, Jan; Lux, Michael P.; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Maleva Kostovska, Ivana; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Martens, John W.M.; Martinez, Maria Elena; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Menon, Usha; Middha, Pooja; Miller, Nicola; Moreno, Fernando; Mulligan, Anna Marie; Mulot, Claire; Muñoz-Garzon, Victor M.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Newman, William G.; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Offit, Kenneth; Olson, Janet E.; Olsson, Håkan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung-Won; Perez, Jose I.A.; Pérez-Barrios, Clara; Peterlongo, Paolo; Peto, Julian; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Polley, Eric C.; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Purrington, Kristen; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rau-Murthy, Rohini; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Robson, Mark; Romero, Atocha; Ruddy, Kathryn J.; Ruebner, Matthias; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J.; Seynaeve, Caroline; Shah, Mitul; Sherman, Mark E.; Shrubsole, Martha J.; Shu, Xiao-Ou; Slager, Susan; Smeets, Ann; Sohn, Christof; Soucy, Penny; Southey, Melissa C.; Spinelli, John J.; Stegmaier, Christa; Stone, Jennifer; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Terry, Mary Beth; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Truong, Thérèse; Tzardi, Maria; Ulmer, Hans-Ulrich; Untch, Michael; Vachon, Celine M.; van Veen, Elke M.; Vijai, Joseph; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Zhang, Yan; Zheng, Wei; Ziogas, Argyrios; Dunning, Alison M.; Thompson, Deborah J.; Chenevix-Trench, Georgia; Chang-Claude, Jenny; Schmidt, Marjanka K.; Hall, Per; Milne, Roger L.; Pharoah, Paul D.P.; Antoniou, Antonis C.; Chatterjee, Nilanjan; Kraft, Peter; García-Closas, Montserrat; Simard, Jacques; Easton, Douglas F. (2019)
    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.
  • Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B.; Barrowdale, Daniel; Dennis, Joe; McGuffog, Lesley; Soucy, Penny; Leslie, Goska; Rizzolo, Piera; Navazio, Anna Sara; Valentini, Virginia; Zelli, Veronica; Lee, Andrew; Al Olama, Ali Amin; Tyrer, Jonathan P.; Southey, Melissa; John, Esther M.; Conner, Thomas A.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Steele, Linda; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Osorio, Ana; Weitzel, Jeffrey N.; Toss, Angela; Medici, Veronica; Cortesi, Laura; Zanna, Ines; Palli, Domenico; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Azzollini, Jacopo; Viel, Alessandra; Cini, Giulia; Damante, Giuseppe; Tommasi, Stefania; Peterlongo, Paolo; Fostira, Florentia; Hamann, Ute; Evans, D. Gareth; Henderson, Alex; Brewer, Carole; Kiiski, Johanna I.; Aittomäki, Kristiina; Khan, Sofia; Nevanlinna, Heli; EMBRACE; GEMO Study Collaborators; HEBON; KConFab Investigators (2017)
    PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.