Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

Alkuperäiskielienglanti
LehtiNature Genetics
Vuosikerta52
Numero1
Sivut56-73
Sivumäärä25
ISSN1061-4036
DOI - pysyväislinkit
TilaJulkaistu - tammikuuta 2020
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lisätietoja

cited By 0

Tieteenalat

  • 1184 Genetiikka, kehitysbiologia, fysiologia

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