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1. Modelling Breakage-Fusion-Bridge Cycles as a Stochastic Paper Folding Process

Author: Greenman, CD, Cooke, SL, Marshall, J, Stratton, MR, and Campbell, PJ
Subjects: Quantitative Biology - Genomics, Mathematics - Combinatorics
Abstract: Breakage-Fusion-Bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then `unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. The process has parallels with paper folding sequences that arise when a piece of paper is folded several times and then unfolded. Here we adapt such methods to study the breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are 2^(n(n-1)/2) qualitatively distinct evolutions involving n breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the fold positions, to determine evolution likelihoods, and also describe how amplicons become localised. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples., Comment: 34 pages, 11 figures
Published: 2012

2. Genomic reconstruction of the SARS-CoV-2 epidemic in England

Author: Vöhringer, HS, Sanderson, T, Sinnott, M, De Maio, N, Nguyen, T, Goater, R, Schwach, F, Harrison, I, Hellewell, J, Ariani, CV, Gonçalves, S, Jackson, DK, Johnston, I, Jung, AW, Saint, C, Sillitoe, J, Suciu, M, Goldman, N, Panovska-Griffiths, J, Abnizova, I, Aigrain, L, Alderton, A, Ali, M, Allen, L, Amato, R, Anderson, R, Ariani, C, Austin-Guest, S, Bala, S, Barrett, J, Bassett, A, Battleday, K, Beal, J, Beale, M, Beaver, C, Bellany, S, Bellerby, T, Bellis, K, Berger, D, Berriman, M, Betteridge, E, Bevan, P, Binley, S, Bishop, J, Blackburn, K, Bonfield, J, Boughton, N, Bowker, S, Brendler-Spaeth, T, Bronner, I, Brooklyn, T, Buddenborg, SK, Bush, R, Caetano, C, Cagan, A, Carter, N, Cartwright, J, Monteiro, TC, Chapman, L, Chillingworth, T-J, Clapham, P, Clark, R, Clarke, A, Clarke, C, Cole, D, Cook, E, Coppola, M, Cornell, L, Cornwell, C, Corton, C, Crackett, A, Cranage, A, Craven, H, Craw, S, Crawford, M, Cutts, T, Dabrowska, M, Davies, M, Davies, R, Dawson, J, Day, C, Densem, A, Dibling, T, Dockree, C, Dodd, D, Dogga, S, Dorman, M, Dougan, G, Dougherty, M, Dove, A, Drummond, L, Drury, E, Dudek, M, Durham, J, Durrant, L, Easthope, E, Eckert, S, Ellis, P, Farr, B, Fenton, M, Ferrero, M, Flack, N, Fordham, H, Forsythe, G, Foulser, L, Francis, M, Fraser, A, Freeman, A, Galvin, A, Garcia-Casado, M, Gedny, A, Girgis, S, Glover, J, Goncalves, S, Goodwin, S, Gould, O, Gourtovaia, M, Gray, A, Gray, E, Griffiths, C, Gu, Y, Guerin, F, Hamilton, W, Hanks, H, Harrison, E, Harrott, A, Harry, E, Harvison, J, Heath, P, Hernandez-Koutoucheva, A, Hobbs, R, Holland, D, Holmes, S, Hornett, G, Hough, N, Huckle, L, Hughes-Hallet, L, Hunter, A, Inglis, S, Iqbal, S, Jackson, A, Jackson, D, James, K, Jamrozy, D, Verdejo, CJ, Jones, M, Kallepally, K, Kane, L, Kay, K, Kay, S, Keatley, J, Keith, A, King, A, Kitchin, L, Kleanthous, M, Klimekova, M, Korlevic, P, Krasheninnkova, K, Lane, G, Langford, C, Laverack, A, Law, K, Lawniczak, M, Lensing, S, Leonard, S, Letchford, L, Lewis, K, Lewis-Wade, A, Liddle, J, Lin, Q, Lindsay, S, Linsdell, S, Livett, R, Lo, S, Long, R, Lovell, J, Ludden, C, Mack, J, Maddison, M, Makunin, A, Mamun, I, Mansfield, J, Marriott, N, Martin, M, Mayho, M, McCarthy, S, McClintock, J, McGuigan, S, McHugh, S, McMinn, L, Meadows, C, Mobley, E, Moll, R, Morra, M, Morrow, L, Murie, K, Nash, S, Nathwani, C, Naydenova, P, Neaverson, A, Nelson, R, Nerou, E, Nicholson, J, Nimz, T, Noell, GG, O’Meara, S, Ohan, V, Oliver, K, Olney, C, Ormond, D, Oszlanczi, A, Palmer, S, Pang, YF, Pardubska, B, Park, N, Parmar, A, Patel, G, Patel, M, Payne, M, Peacock, S, Petersen, A, Plowman, D, Preston, T, Prestwood, L, Puethe, C, Quail, M, Rajan, D, Rajatileka, S, Rance, R, Rawlings, S, Redshaw, N, Reynolds, J, Reynolds, M, Rice, S, Richardson, M, Roberts, C, Robinson, K, Robinson, M, Robinson, D, Rogers, H, Rojo, EM, Roopra, D, Rose, M, Rudd, L, Sadri, R, Salmon, N, Saul, D, Scott, C, Seekings, P, Shirley, L, Simms, A, Sivadasan, S, Siwek, B, Sizer, D, Skeldon, K, Skelton, J, Slater-Tunstill, J, Sloper, L, Smerdon, N, Smith, C, Smith, J, Smith, K, Smith, M, Smith, S, Smith, T, Sneade, L, Soria, CD, Sousa, C, Souster, E, Sparkes, A, Spencer-Chapman, M, Squares, J, Stanley, R, Steed, C, Stickland, T, Still, I, Stratton, MR, Strickland, M, Swann, A, Swiatkowska, A, Sycamore, N, Swift, E, Symons, E, Szluha, S, Taluy, E, Tao, N, Taylor, K, Taylor, S, Thompson, S, Thompson, M, Thomson, M, Thomson, N, Thurston, S, Tonkin-Hill, G, Toombs, D, Topping, B, Tovar-Corona, J, Ungureanu, D, Uphill, J, Urbanova, J, Van Vuuren, PJ, Vancollie, V, Voak, P, Walker, D, Walker, M, Waller, M, Ward, G, Weatherhogg, C, Webb, N, Weldon, D, Wells, A, Wells, E, Westwood, L, Whipp, T, Whiteley, T, Whitton, G, Whitwham, A, Widaa, S, Williams, M, Wilson, M, Wright, S, Robson, SC, Connor, TR, Loman, NJ, Golubchik, T, Martinez Nunez, RT, Bonsall, D, Rambaut, A, Snell, LB, Corden, S, Nastouli, E, Nebbia, G, Lythgoe, K, Torok, ME, Goodfellow, IG, Prieto, JA, Saeed, K, Houlihan, C, Frampton, D, Hamilton, WL, Witney, AA, Bucca, G, Pope, CF, Moore, C, Thomson, EC, Harrison, EM, Smith, CP, Rogan, F, Beckwith, SM, Murray, A, Singleton, D, Eastick, K, Sheridan, LA, Randell, P, Jackson, LM, Fairley, DJ, Loose, MW, Watkins, J, Moses, S, Nicholls, S, Bull, M, Smith, DL, Aanensen, DM, Aggarwal, D, Shepherd, JG, Curran, MD, Parmar, S, Parker, MD, Williams, C, Glaysher, S, Underwood, AP, Bashton, M, Pacchiarini, N, Loveson, KF, Byott, M, Carabelli, AM, Templeton, KE, de Silva, TI, Wang, D, Langford, CF, Gunson, RN, Cottrell, S, O’Grady, J, Kwiatkowski, D, Lillie, PJ, Cortes, N, Moore, N, Thomas, C, Burns, PJ, Mahungu, TW, Liggett, S, Beckett, AH, Holden, MTG, Levett, LJ, Osman, H, Hassan-Ibrahim, MO, Simpson, DA, Chand, M, Gupta, RK, Darby, AC, Paterson, S, Pybus, OG, Volz, EM, de Angelis, D, Robertson, DL, Page, AJ, Bassett, AR, Wong, N, Taha, Y, Erkiert, MJ, Spencer Chapman, MH, Dewar, R, McHugh, MP, Mookerjee, S, Aplin, S, Harvey, M, Sass, T, Umpleby, H, Wheeler, H, McKenna, JP, Warne, B, Taylor, JF, Chaudhry, Y, Izuagbe, R, Jahun, AS, Young, GR, McMurray, C, McCann, CM, Nelson, A, Elliott, S, Lowe, H, Price, A, Crown, MR, Rey, S, Roy, S, Temperton, B, Shaaban, S, Hesketh, AR, Laing, KG, Monahan, IM, Heaney, J, Pelosi, E, Silviera, S, Wilson-Davies, E, Fryer, H, Adams, H, du Plessis, L, Johnson, R, Harvey, WT, Hughes, J, Orton, RJ, Spurgin, LG, Bourgeois, Y, Ruis, C, O’Toole, Á, Fraser, C, Edgeworth, J, Breuer, J, Michell, SL, Todd, JA, John, M, Buck, D, Gajee, K, Kay, GL, Peacock, SJ, Heyburn, D, Kitchman, K, McNally, A, Pritchard, DT, Dervisevic, S, Muir, P, Robinson, E, Vipond, BB, Ramadan, NA, Jeanes, C, Catalan, J, Jones, N, da Silva Filipe, A, Fuchs, M, Miskelly, J, Jeffries, AR, Park, NR, Ash, A, Koshy, C, Barrow, M, Buchan, SL, Mantzouratou, A, Clark, G, Holmes, CW, Campbell, S, Davis, T, Tan, NK, Brown, JR, Harris, KA, Kidd, SP, Grant, PR, Xu-McCrae, L, Cox, A, Madona, P, Pond, M, Randell, PA, Withell, KT, Graham, C, Denton-Smith, R, Swindells, E, Turnbull, R, Sloan, TJ, Bosworth, A, Hutchings, S, Pymont, HM, Casey, A, Ratcliffe, L, Jones, CR, Knight, BA, Haque, T, Hart, J, Irish-Tavares, D, Witele, E, Mower, C, Watson, LK, Collins, J, Eltringham, G, Crudgington, D, Macklin, B, Iturriza-Gomara, M, Lucaci, AO, McClure, PC, Carlile, M, Holmes, N, Storey, N, Rooke, S, Yebra, G, Craine, N, Perry, M, Alikhan, N-F, Bridgett, S, Cook, KF, Fearn, C, Goudarzi, S, Lyons, RA, Williams, T, Haldenby, ST, Davies, RM, Batra, R, Blane, B, Spyer, MJ, Smith, P, Yavus, M, Williams, RJ, Mahanama, AIK, Samaraweera, B, Girgis, ST, Hansford, SE, Green, A, Bellis, KL, Dorman, MJ, Quick, J, Poplawski, R, Reynolds, N, Mack, A, Morriss, A, Whalley, T, Patel, B, Georgana, I, Hosmillo, M, Pinckert, ML, Stockton, J, Henderson, JH, Hollis, A, Stanley, W, Yew, WC, Myers, R, Thornton, A, Adams, A, Annett, T, Asad, H, Birchley, A, Coombes, J, Evans, JM, Fina, L, Gatica-Wilcox, B, Gilbert, L, Graham, L, Hey, J, Hilvers, E, Jones, S, Jones, H, Kumziene-Summerhayes, S, McKerr, C, Powell, J, Pugh, G, Trotter, AJ, Williams, CA, Kermack, LM, Foulkes, BH, Gallis, M, Hornsby, HR, Louka, SF, Pohare, M, Wolverson, P, Zhang, P, MacIntyre-Cockett, G, Trebes, A, Moll, RJ, Ferguson, L, Goldstein, EJ, Maclean, A, Tomb, R, Starinskij, I, Thomson, L, Southgate, J, Kraemer, MUG, Raghwani, J, Zarebski, AE, Boyd, O, Geidelberg, L, Illingworth, CJ, Jackson, C, Pascall, D, Vattipally, S, Freeman, TM, Hsu, SN, Lindsey, BB, Tovar-Corona, JM, Cox, M, Abudahab, K, Menegazzo, M, Taylor, BEW, Yeats, CA, Mukaddas, A, Wright, DW, de Oliveira Martins, L, Colquhoun, R, Hill, V, Jackson, B, McCrone, JT, Medd, N, Scher, E, Keatley, J-P, Curran, T, Morgan, S, Maxwell, P, Eldirdiri, S, Kenyon, A, Holmes, AH, Price, JR, Wyatt, T, Mather, AE, Skvortsov, T, Hartley, JA, Guest, M, Kitchen, C, Merrick, I, Munn, R, Bertolusso, B, Lynch, J, Vernet, G, Kirk, S, Wastnedge, E, Idle, G, Bradley, DT, Poyner, J, Mori, M, Jones, O, Wright, V, Brooks, E, Churcher, CM, Fragakis, M, Galai, K, Jermy, A, Judges, S, McManus, GM, Smith, KS, Westwick, E, Attwood, SW, Bolt, F, Davies, A, De Lacy, E, Downing, F, Edwards, S, Meadows, L, Jeremiah, S, Smith, N, Charalampous, T, Patel, A, Berry, L, Boswell, T, Fleming, VM, Howson-Wells, HC, Joseph, A, Khakh, M, Lister, MM, Bird, PW, Fallon, K, Helmer, T, McMurray, CL, Odedra, M, Shaw, J, Tang, JW, Willford, NJ, Blakey, V, Raviprakash, V, Sheriff, N, Williams, L-A, Feltwell, T, Bedford, L, Cargill, JS, Hughes, W, Moore, J, Stonehouse, S, Atkinson, L, Lee, JCD, Shah, D, Alcolea, A, Ohemeng-Kumi, N, Ramble, J, Sehmi, J, Williams, R, Chatterton, W, Pusok, M, Everson, W, Castigador, A, Macnaughton, E, El Bouzidi, K, Lampejo, T, Sudhanva, M, Breen, C, Sluga, G, Ahmad, SSY, George, RP, Machin, NW, Binns, D, James, V, Blacow, R, Coupland, L, Smith, L, Barton, E, Padgett, D, Scott, G, Cross, A, Mirfenderesky, M, Greenaway, J, Cole, K, Clarke, P, Duckworth, N, Walsh, S, Bicknell, K, Impey, R, Wyllie, S, Hopes, R, Bishop, C, Chalker, V, Gifford, L, Molnar, Z, Auckland, C, Evans, C, Johnson, K, Partridge, DG, Raza, M, Baker, P, Bonner, S, Essex, S, Murray, LJ, Lawton, AI, Burton-Fanning, S, Payne, BAI, Waugh, S, Gomes, AN, Kimuli, M, Murray, DR, Ashfield, P, Dobie, D, Ashford, F, Best, A, Crawford, L, Cumley, N, Mayhew, M, Megram, O, Mirza, J, Moles-Garcia, E, Percival, B, Ensell, L, Lowe, HL, Maftei, L, Mondani, M, Chaloner, NJ, Cogger, BJ, Easton, LJ, Huckson, H, Lewis, J, Lowdon, S, Malone, CS, Munemo, F, Mutingwende, M, Nicodemi, R, Podplomyk, O, Somassa, T, Beggs, A, Richter, A, Cormie, C, Dias, J, Forrest, S, Higginson, EE, Maes, M, Young, J, Davidson, RK, Jackson, KA, Turtle, L, Keeley, AJ, Ball, J, Byaruhanga, T, Chappell, JG, Dey, J, Hill, JD, Park, EJ, Fanaie, A, Hilson, RA, Yaze, G, Afifi, S, Beer, R, Maksimovic, J, Masters, KM, Spellman, K, Bresner, C, Fuller, W, Marchbank, A, Workman, T, Shelest, E, Debebe, J, Sang, F, Zamudio, ME, Francois, S, Gutierrez, B, Vasylyeva, TI, Flaviani, F, Ragonnet-Cronin, M, Smollett, KL, Broos, A, Mair, D, Nichols, J, Nomikou, K, Tong, L, Tsatsani, I, O’Brien, S, Rushton, S, Sanderson, R, Perkins, J, Cotton, S, Gallagher, A, Allara, E, Pearson, C, Bibby, D, Dabrera, G, Ellaby, N, Gallagher, E, Hubb, J, Lackenby, A, Lee, D, Manesis, N, Mbisa, T, Platt, S, Twohig, KA, Morgan, M, Aydin, A, Baker, DJ, Foster-Nyarko, E, Prosolek, SJ, Rudder, S, Baxter, C, Carvalho, SF, Lavin, D, Mariappan, A, Radulescu, C, Singh, A, Tang, M, Morcrette, H, Bayzid, N, Cotic, M, Balcazar, CE, Gallagher, MD, Maloney, D, Stanton, TD, Williamson, KA, Manley, R, Michelsen, ML, Sambles, CM, Studholme, DJ, Warwick-Dugdale, J, Eccles, R, Gemmell, M, Gregory, R, Hughes, M, Nelson, C, Rainbow, L, Vamos, EE, Webster, HJ, Whitehead, M, Wierzbicki, C, Angyal, A, Green, LR, Whiteley, M, Bronner, IF, Farr, BW, Lensing, SV, McCarthy, SA, Quail, MA, Redshaw, NM, Thurston, SAJ, Rowe, W, Gaskin, A, Le-Viet, T, Birney, E, Volz, E, Funk, S, Martincorena, I, Barrett, JC, and Gerstung, M
Abstract: The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.
Published: 2021

3. Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Author: Brinkman, AB, Nik-Zainal, S, Simmer, F, Rodriguez Gonzalez, Francisco, Smid, Marcel, Alexandrov, LB, Butler, A, Martink, S, Davies, H, Glodzik, D, Zou, X Q, Ramakrishna, M, Staaf, J, Ringrier, M, Sieuwerts, Anieta, Ferrari, A, Morganella, S, Fleischer, T, Kristensen, V, Gut, M, van de Vijver, MJ, Borresen-Dale, AL, Richardson, AL, Thomas, G, Gut, I G, Martens, John, Foekens, John, Stratton, MR, Stunnenberg, HG, Brinkman, AB, Nik-Zainal, S, Simmer, F, Rodriguez Gonzalez, Francisco, Smid, Marcel, Alexandrov, LB, Butler, A, Martink, S, Davies, H, Glodzik, D, Zou, X Q, Ramakrishna, M, Staaf, J, Ringrier, M, Sieuwerts, Anieta, Ferrari, A, Morganella, S, Fleischer, T, Kristensen, V, Gut, M, van de Vijver, MJ, Borresen-Dale, AL, Richardson, AL, Thomas, G, Gut, I G, Martens, John, Foekens, John, Stratton, MR, and Stunnenberg, HG
Published: 2019

4. Science Forum: The Human Cell Atlas

Author: Regev, A, Teichmann, SA, Lander, ES, Amit, I, Benoist, C, Birney, E, Bodenmiller, B, Campbell, PJ, Carninci, P, Clatworthy, M, Clevers, H, Deplancke, B, Dunham, I, Eberwine, J, Eils, R, Enard, W, Farmer, A, Fugger, L, Göttgens, B, Hacohen, N, Haniffa, M, Hemberg, M, Kim, SK, Klenerman, P, Kriegstein, A, Lein, E, Linnarsson, S, Lundberg, E, Lundeberg, J, Majumder, P, Marioni, JC, Merad, M, Mhlanga, M, Nawijn, M, Netea, M, Nolan, G, Pe'er, D, Phillipakis, A, Ponting, CP, Quake, SR, Reik, W, Rozenblatt-Rosen, O, Sanes, JR, Satija, R, Schumacher, TN, Shalek, AK, Shapiro, E, Sharma, P, Shin, JW, Stegle, O, Stratton, MR, Stubbington, MJT, Theis, FJ, Uhlen, M, van Oudenaarden, A, Wagner, A, Watt, FM, Weissman, JS, Wold, BJ, Xavier, RJ, and Yosef, N
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
Published: 2018

5. Abstract P4-09-04: Withdrawn

Author: Lonning, PE, primary, Helwa, R, additional, Birkeland, EE, additional, Yates, LR, additional, Wedge, DC, additional, Lokkevik, E, additional, Eikesdal, HP, additional, Stratton, MR, additional, Campbell, PJ, additional, and Knappskog, S, additional
Published: 2018
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6. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author: Glodzik, D, Morganella, S, Davies, H, Simpson, PT, Li, YL, Zou, X Q, Diez-Perez, J, Staaf, J, Alexandrov, LB, Smid, Marcel, Brinkman, AB, Rye, IH, Russnes, H, Raine, K, Purdie, CA, Lakhani, SR, Thompson, AM, Birney, E, Stunnenberg, HG, van de Vijver, MJ, Martens, John, Borresen-Dale, AL, Richardson, AL, Kong, G, Viari, A, Easton, D, Evan, G, Campbell, PJ, Stratton, MR, Nik-Zainal, S, Glodzik, D, Morganella, S, Davies, H, Simpson, PT, Li, YL, Zou, X Q, Diez-Perez, J, Staaf, J, Alexandrov, LB, Smid, Marcel, Brinkman, AB, Rye, IH, Russnes, H, Raine, K, Purdie, CA, Lakhani, SR, Thompson, AM, Birney, E, Stunnenberg, HG, van de Vijver, MJ, Martens, John, Borresen-Dale, AL, Richardson, AL, Kong, G, Viari, A, Easton, D, Evan, G, Campbell, PJ, Stratton, MR, and Nik-Zainal, S
Published: 2017

7. Genomic Evolution of Breast Cancer Metastasis and Relapse

Author: Yates, LR, Knappskog, S, Wedge, D, Farmery, JHR, Gonzalez, S, Martincorena, I, Alexandrov, LB, van Loo, P, Haugland, HK, Lilleng, PK, Gundem, G, Gerstung, M, Pappaemmanuil, E, Gazinska, P, Bhosle, SG, Jones, D, Raine, K, Mudie, L, Latimer, C, Sawyer, E, Desmedt, C, Sotiriou, C, Stratton, MR, Sieuwerts, Anieta, Lynch, AG, Martens, John, Richardson, AL, Tutt, A, Lonning, PE, Campbell, PJ, Yates, LR, Knappskog, S, Wedge, D, Farmery, JHR, Gonzalez, S, Martincorena, I, Alexandrov, LB, van Loo, P, Haugland, HK, Lilleng, PK, Gundem, G, Gerstung, M, Pappaemmanuil, E, Gazinska, P, Bhosle, SG, Jones, D, Raine, K, Mudie, L, Latimer, C, Sawyer, E, Desmedt, C, Sotiriou, C, Stratton, MR, Sieuwerts, Anieta, Lynch, AG, Martens, John, Richardson, AL, Tutt, A, Lonning, PE, and Campbell, PJ
Published: 2017

8. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Author: Burton, PR, Clayton, DG, Cardon, LR, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Samani, NJ, Todd, JA, Donnelly, P, Barrett, JC, Davison, D, Easton, D, Evans, DM, Leung, HT, Marchini, JL, Morris, AP, Spencer, CC, Tobin, MD, Attwood, AP, Boorman, JP, Cant, B, Everson, U, Hussey, JM, Jolley, JD, Knight, AS, Koch, K, Meech, E, Nutland, S, Prowse, CV, Stevens, HE, Taylor, NC, Walters, GR, Walker, NM, Watkins, NA, Winzer, T, Jones, RW, McArdle, WL, Ring, SM, Strachan, DP, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon-Smith, K, Jones, L, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskivina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGuffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, TD, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Thompson, JR, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Forbes, A, Lewis, CM, Onnie, CM, Prescott, NJ, Sanderson, J, Matthew, CG, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Webster, J, Brown, MJ, Lathrop, MG, Connell, J, Dominiczak, A, Marcano, CA, Burke, B, Dobson, R, Gungadoo, J, Lee, KL, Munroe, PB, Newhouse, SJ, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hilder, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DP, Thomson, W, Worthington, J, Dunger, DB, Widmer, B, Frayling, TM, Freathy, RM, Lango, H, Perry, JR, Shields, BM, Weedon, MN, Hattersley, AT, Hitman, GA, Walker, M, Elliott, KS, Groves, CJ, Lindgren, CM, Rayner, NW, Timpson, NJ, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, AV, Bradbury, LA, Farrar, C, Pointon, JJ, Wordsworth, P, Brown, MA, Franklyn, JA, Heward, JM, Simmonds, MJ, Gough, SC, Seal, S, Stratton, MR, Rahman, N, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Conway, D, Jallow, M, Rockett, KA, Bumpstead, SJ, Chaney, A, Downes, K, Ghori, MJ, Gwilliam, R, Hunt, SE, Inouye, M, Keniry, A, King, E, McGinnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Withers, D, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdo'ttir, IB, Howie, BN, Su, Z, Teo, YY, Vukcevic, D, Bentley, D, Mitchell, SL, Newby, PR, Brand, OJ, Carr-Smith, J, Pearce, SH, Reveille, JD, Zhou, X, Sims, AM, Dowling, A, Taylor, J, Doan, T, Davis, JC, Savage, L, Ward, MM, Learch, TL, Weisman, MH, and Brown, M
Subjects: Linkage disequilibrium, Multiple Sclerosis, Genotype, Population, Single-nucleotide polymorphism, Genome-wide association study, Autoimmunity, Breast Neoplasms, Biology, medicine.disease_cause, Aminopeptidases, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Minor Histocompatibility Antigens, Genetics, medicine, Humans, Spondylitis, Ankylosing, Receptors, Immunologic, education, Genetic association, education.field_of_study, Ankylosing spondylitis, Thyroiditis, Autoimmune, Chromosome Mapping, Receptors, Interleukin, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Genetics, Population, Haplotypes, Case-Control Studies, Immunology, North America
Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
Published: 2016

9. Hypothesis-based analysis of gene-gene interactions and risk of myocardial infarction

Author: Lucas G1, Lluís-Ganella C, Subirana I, Musameh MD, Gonzalez JR, Nelson CP, Sentí M, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Schwartz SM, Siscovick D, O'Donnell CJ, Melander O, Salomaa V, Purcell S, Altshuler D, Samani NJ, Kathiresan S, Elosua R, Voight BF, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, Peltonen L, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Yee J, Friedlander Y, Marrugat J, Lucas G, Sala J, Ramos R, Meigs JB, Williams G, Nathan DM, MacRae CA, Havulinna AS, Berglund G, Deloukas P, Donnelly P, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Kwiatkowski DP, Mathew CG, McCarthy MI, Ouwehand WH, Parkes M, Pembrey M, Rahman N, Stratton MR, Todd JA, Worthington J, Burton PR, Clayton DG, Cardon LR, Craddock N, Duncanson A, Barrett JC, Davison D, Easton D, Evans D, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Ball SG, Balmforth AJ, Barrett JH, Bishop D, Iles MM, Maqbool A, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Cardo LR, Cardin NJ, Ferreira T, Pereira-Gale J, Hallgrimsdottir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Lucas, G1, Lluís-Ganella, C, Subirana, I, Musameh, Md, Gonzalez, Jr, Nelson, Cp, Sentí, M, Myocardial Infarction Genetics, Consortium, Wellcome Trust Case Control, Consortium, Schwartz, Sm, Siscovick, D, O'Donnell, Cj, Melander, O, Salomaa, V, Purcell, S, Altshuler, D, Samani, Nj, Kathiresan, S, Elosua, R, Voight, Bf, Musunuru, K, Ardissino, D, Mannucci, Pm, Anand, S, Engert, Jc, Schunkert, H, Erdmann, J, Reilly, Mp, Rader, Dj, Morgan, T, Spertus, Ja, Stoll, M, Girelli, D, Mckeown, Pp, Patterson, Cc, Peltonen, L, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Yee, J, Friedlander, Y, Marrugat, J, Lucas, G, Sala, J, Ramos, R, Meigs, Jb, Williams, G, Nathan, Dm, Macrae, Ca, Havulinna, A, Berglund, G, Deloukas, P, Donnelly, P, Farrall, M, Gough, Sc, Hall, A, Hattersley, At, Hill, Av, Kwiatkowski, Dp, Mathew, Cg, Mccarthy, Mi, Ouwehand, Wh, Parkes, M, Pembrey, M, Rahman, N, Stratton, Mr, Todd, Ja, Worthington, J, Burton, Pr, Clayton, Dg, Cardon, Lr, Craddock, N, Duncanson, A, Barrett, Jc, Davison, D, Easton, D, Evans, D, Leung, Ht, Marchini, Jl, Morris, Ap, Spencer, Cc, Tobin, Md, Attwood, Ap, Boorman, Jp, Cant, B, Everson, U, Hussey, Jm, Jolley, Jd, Knight, A, Koch, K, Meech, E, Nutland, S, Prowse, Cv, Stevens, He, Taylor, Nc, Walters, Gr, Walker, Nm, Watkins, Na, Winzer, T, Jones, Rw, Mcardle, Wl, Ring, Sm, Strachan, Dp, Ball, Sg, Balmforth, Aj, Barrett, Jh, Bishop, D, Iles, Mm, Maqbool, A, Braund, P, Dixon, Rj, Mangino, M, Stevens, S, Thompson, Jr, Bumpstead, Sj, Chaney, A, Downes, K, Ghori, Mj, Gwilliam, R, Hunt, Se, Inouye, M, Keniry, A, King, E, Mcginnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Cardo, Lr, Cardin, Nj, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, Ib, Howie, Bn, Su, Z, Teo, Yy, and Vukcevic, D
Subjects: Heredity, Epidemiology, Myocardial Infarction, lcsh:Medicine, Genome-wide association study, Coronary Artery Disease, Cardiovascular, Logistic regression, Risk Factors, Cardiac and Cardiovascular Systems, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Medicine (all), 030305 genetics & heredity, Genomics, Genetic Epidemiology, Medicine, Research Article, Human, Risk, Genotype, Genotypes, Reproducibility of Result, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome Analysis Tools, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Risk factor, Allele frequency, Genetic Association Studies, 030304 developmental biology, Genetic association, Biochemistry, Genetics and Molecular Biology (all), Complex Traits, Risk Factor, lcsh:R, Reproducibility of Results, Human Genetics, Epistasis, Genetic, Odds ratio, Genetic epidemiology, Agricultural and Biological Sciences (all), Genetics of Disease, Epistasis, Genetic Polymorphism, Infart de miocardi -- Epidemiologia, lcsh:Q, Population Genetics, Genome-Wide Association Study
Abstract: The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3–2.0, depending on allele frequency and interaction model).
Published: 2012

10. The topography of mutational processes in breast cancer genomes

Author: Morganella, S, Alexandrov, LB, Glodzik, D, Zou, X Q, Davies, H, Staaf, J, Sieuwerts, Anieta, Brinkman, AB, Martin, S, Ramakrishna, M, Butler, A, Kim, H Y, Borg, A, Sotiriou, C, Futreal, PA, Campbell, PJ, Span, PN, van Laere, S, Lakhani, SR, Eyfjord, JE, Thompson, AM, Stunnenberg, HG, de Vijver, MJV, Martens, John, Borresen-Dale, AL, Richardson, AL, Kong, G, Thomas, G, Sale, J, Rada, C, Stratton, MR, Birney, E, Nik-Zainal, S, Morganella, S, Alexandrov, LB, Glodzik, D, Zou, X Q, Davies, H, Staaf, J, Sieuwerts, Anieta, Brinkman, AB, Martin, S, Ramakrishna, M, Butler, A, Kim, H Y, Borg, A, Sotiriou, C, Futreal, PA, Campbell, PJ, Span, PN, van Laere, S, Lakhani, SR, Eyfjord, JE, Thompson, AM, Stunnenberg, HG, de Vijver, MJV, Martens, John, Borresen-Dale, AL, Richardson, AL, Kong, G, Thomas, G, Sale, J, Rada, C, Stratton, MR, Birney, E, and Nik-Zainal, S
Published: 2016

11. CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies

Author: Easton, D, McGuffog, L, Thompson, D, Dunning, AJ, Tee, L, Baynes, C, Healey, C, Pharoah, P, Ponder, BAJ, Seal, S, Barfoot, R, Sodha, N, Eeles, R, Stratton, MR, Rahman, N, Peto, J, Spurdle, AB, Chen, X, Chenevix-Trench, G, Hopper, JL, Giles, GG, McCredie, MRE, Syrjakoski, K, Holli, K, Kallioniemi, O-P, Eerola, H, Vahteristo, P, Blomqvist, C, Nevanlinna, H, Kataja, V, Mannermaa, A, Dork, T, Bremer, M, Deviljee, P, de Bock, GH, Krol-Warmerdam, EMM, Kroese-Jansema, K, Wijers-Koster, P, Cornelisse, CJ, Tollenaart, RAEM, Meijers-Heijboer, EJ, Berns, Els, Nagel, J, Foekens, John, Klijn, Jan, Schutte, Mieke, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Human Genetics, Clinical Genetics, and Medical Oncology
Subjects: Adult, LI-FRAUMENI-SYNDROME, PENETRANCE, Genotype, Breast Neoplasms, Protein Serine-Threonine Kinases, SDG 3 - Good Health and Well-being, Risk Factors, Odds Ratio, Genetics, Humans, Genetic Predisposition to Disease, BRCA2 MUTATIONS, skin and connective tissue diseases, Genetics (clinical), POPULATION, CHEK2, Aged, Sequence Deletion, RISK, WOMEN, Articles, Middle Aged, SERIES, GENE, Gene Expression Regulation, Neoplastic, Checkpoint Kinase 2, Genetics, Population, Case-Control Studies, Female, CHECKPOINT
Abstract: Previous studies of families with multiple cases of breast cancer have indicated that a frameshift alteration in the CHEK2 gene, 1100delC, is associated with an elevated frequency of breast cancer in such families, but the risk associated with the variant in other situations is uncertain. To evaluate the breast cancer risk associated with this variant, 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in five countries were genotyped. CHEK2*1100delC was found in 201 cases (1.9%) and 64 controls (0.7%) (estimated odds ratio 2.34; 95% CI 1.72–3.20; P=.0000001). There was some evidence of a higher prevalence of CHEK2*1100delC among cases with a first-degree relative affected with breast cancer (odds ratio 1.44; 95% CI 0.93–2.23; P=.10) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis (P=.002). These results confirm that CHEK2*1100delC confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results are consistent with the hypothesis that CHEK2*1100delC multiplies the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.
Published: 2004

12. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

Author: Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN, Burnett MS, Devaney JM, Knouff CW, Thompson JR, Horne BD, Stewart AF, Assimes TL, Wild PS, Allayee H, Nitschke PL, Patel RS, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Martinelli N, Girelli D, Quyyumi AA, Anderson JL, Erdmann J, Hall AS, Schunkert H, Quertermous T, Blankenberg S, Hazen SL, Roberts R, Kathiresan S, Samani NJ, Epstein SE, Rader DJ, Qasim AN, DerOhannessian SL, Qu L, Cappola TP, Chen Z, Matthai W, Hakonarson HH, Wilensky R, Kent KM, Lindsay JM, Pichard AD, Satler L, Waksman R, Knoupf CW, Walker MC, Waterworth DM, Mosser V, Braund PS, Wright B, Balmforth AJ, Ball SG, Chen L, Wells GA, McPherson R, Lackner K, Munzel TF, Schillert A, Schnabel R, Zeller T, Ziegler A, Absher D, Hlatky MA, Iribaren C, Knowles JW, Linsel Nitschke P, König IR, Hengstenberg C, Nahrstaedt J, Peters A, Schreiber S, Wichmann E, Willenborg C, Su S, Bouzyk M, Vaccarino V, Zafari AM, Carlquist JF, Muhlestein JB, Olivieri O, Barnard J, Hartiala J, Tang WH, Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Barrett JH, Bishop DT, Iles MM, Maqbool A, Yuldasheva N, Dixon RJ, Mangino M, Stevens S, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop M, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Ferreira T, Pereira Gale J, Hallgrimsdóttir IB, Bowie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, CASARI , GIORGIO NEVIO, Reilly, Mp, Li, M, He, J, Ferguson, Jf, Stylianou, Im, Mehta, Nn, Burnett, M, Devaney, Jm, Knouff, Cw, Thompson, Jr, Horne, Bd, Stewart, Af, Assimes, Tl, Wild, P, Allayee, H, Nitschke, Pl, Patel, R, Myocardial Infarction Genetics, Consortium, Wellcome Trust Case Control, Consortium, Martinelli, N, Girelli, D, Quyyumi, Aa, Anderson, Jl, Erdmann, J, Hall, A, Schunkert, H, Quertermous, T, Blankenberg, S, Hazen, Sl, Roberts, R, Kathiresan, S, Samani, Nj, Epstein, Se, Rader, Dj, Qasim, An, Derohannessian, Sl, Qu, L, Cappola, Tp, Chen, Z, Matthai, W, Hakonarson, Hh, Wilensky, R, Kent, Km, Lindsay, Jm, Pichard, Ad, Satler, L, Waksman, R, Knoupf, Cw, Walker, Mc, Waterworth, Dm, Mosser, V, Braund, P, Wright, B, Balmforth, Aj, Ball, Sg, Chen, L, Wells, Ga, Mcpherson, R, Lackner, K, Munzel, Tf, Schillert, A, Schnabel, R, Zeller, T, Ziegler, A, Absher, D, Hlatky, Ma, Iribaren, C, Knowles, Jw, Linsel Nitschke, P, König, Ir, Hengstenberg, C, Nahrstaedt, J, Peters, A, Schreiber, S, Wichmann, E, Willenborg, C, Su, S, Bouzyk, M, Vaccarino, V, Zafari, Am, Carlquist, Jf, Muhlestein, Jb, Olivieri, O, Barnard, J, Hartiala, J, Tang, Wh, Burton, Pr, Clayton, Dg, Cardon, Lr, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, Dp, Mccarthy, Mi, Ouwehand, Wh, Todd, Ja, Donnelly, P, Barrett, Jc, Davison, D, Easton, D, Evans, Dm, Leung, Ht, Marchini, Jl, Morris, Ap, Spencer, Cc, Tobin, Md, Attwood, Ap, Boorman, Jp, Cant, B, Everson, U, Hussey, Jm, Jolley, Jd, Knight, A, Koch, K, Meech, E, Nutland, S, Prowse, Cv, Stevens, He, Taylor, Nc, Walters, Gr, Walker, Nm, Watkins, Na, Winzer, T, Jones, Rw, Mcardle, Wl, Ring, Sm, Strachan, Dp, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon Smith, K, Jones, L, Fraser, C, Green, Ek, Grozeva, D, Hamshere, Ml, Holmans, Pa, Jones, Ir, Kirov, G, Moskvina, V, Nikolov, I, O'Donovan, Mc, Owen, Mj, Collier, Da, Elkin, A, Farmer, A, Williamson, R, Mcguffin, P, Young, Ah, Ferrier, In, Barrett, Jh, Bishop, Dt, Iles, Mm, Maqbool, A, Yuldasheva, N, Dixon, Rj, Mangino, M, Stevens, S, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, Cw, Nimmo, Er, Satsangi, J, Fisher, Sa, Forbes, A, Lewis, Cm, Onnie, Cm, Prescott, Nj, Sanderson, J, Mathew, Cg, Barbour, J, Mohiuddin, Mk, Todhunter, Ce, Mansfield, Jc, Ahmad, T, Cummings, Fr, Jewell, Dp, Webster, J, Brown, Mj, Lathrop, M, Connell, J, Dominiczak, A, Marcano, Ca, Burke, B, Dobson, R, Gungadoo, J, Lee, Kl, Munroe, Pb, Newhouse, Sj, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, In, Donovan, H, Eyre, S, Gilbert, Pd, Hider, Sl, Hinks, Am, John, Sl, Potter, C, Silman, Aj, Symmons, Dp, Thomson, W, Worthington, J, Dunger, Db, Widmer, B, Frayling, Tm, Freathy, Rm, Lango, H, Perry, Jr, Shields, Bm, Weedon, Mn, Hattersley, At, Hitman, Ga, Walker, M, Elliott, K, Groves, Cj, Lindgren, Cm, Rayner, Nw, Timpson, Nj, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, Av, Bradbury, La, Farrar, C, Pointon, Jj, Wordsworth, P, Brown, Ma, Franklyn, Ja, Heward, Jm, Simmonds, Mj, Gough, Sc, Seal, S, Stratton, Mr, Rahman, N, Ban, M, Goris, A, Sawcer, Sj, Compston, A, Conway, D, Jallow, M, Rockett, Ka, Bumpstead, Sj, Chaney, A, Downes, K, Ghori, Mj, Gwilliam, R, Hunt, Se, Inouye, M, Keniry, A, King, E, Mcginnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Withers, D, Cardin, Nj, Ferreira, T, Pereira Gale, J, Hallgrimsdóttir, Ib, Bowie, Bn, Su, Z, Teo, Yy, Vukcevic, D, Bentley, D, Meigs, Jb, Williams, G, Nathan, Dm, Macrae, Ca, O'Donnell, Cj, Ardissino, D, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, GIORGIO NEVIO, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Mannucci, Pm, Schwartz, Sm, Siscovick, D, Yee, J, Friedlander, Y, Elosua, R, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Salomaa, V, Havulinna, A, Peltonen, L, Melander, O, Berglund, G, Voight, Bf, Hirschhorn, Jn, Asselta, R, Duga, S, Spreafico, M, Musunuru, K, Daly, Mj, Purcell, S, Surti, A, Guiducci, C, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, and Gabriel, Sb
Subjects: Adult, Male, medicine.medical_specialty, Linkage disequilibrium, ABO, ADAMTS7 Protein, ADAMTS7, Genome-wide association study, Coronary Angiography, Polymorphism, Single Nucleotide, Linkage Disequilibrium, ABO Blood-Group System, Coronary artery disease, Gene Frequency, ABO blood group system, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genetic risk factor, genetic locus, Coronary atherosclerosis, Aged, business.industry, coronary atherosclerosis, General Medicine, Middle Aged, medicine.disease, ADAM Proteins, myocardial infarction, Genetic Loci, Cardiology, Myocardial infarction complications, Female, business, coronary artery disease, Genome-Wide Association Study
Abstract: BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
Published: 2011

13. Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

Author: Schutte, Mieke, Seal, S, Barfoot, R, Meijers-Heijboer, EJ, Wasielewski, M (Marijke), Evans, DG, Eccles, D, Meijers, C, Lohman, FP, Klijn, Jan, van den Ouweland, Ans, Breast cancer Linkage Consor.,, Futreal, PA, Nathanson, KL, Weber, BL, Easton, DF, Stratton, MR, Rahman, N, Medical Oncology, Clinical Genetics, Pediatric Surgery, and Human Genetics
Subjects: Male, Breast Neoplasms, Protein Serine-Threonine Kinases, Biology, Germline, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, Gene Frequency, SDG 3 - Good Health and Well-being, Genetics, Genetic predisposition, medicine, Humans, Genetics(clinical), Genetic Predisposition to Disease, Allele, Risk factor, skin and connective tissue diseases, Allele frequency, CHEK2, Germ-Line Mutation, Genetics (clinical), Sequence Deletion, 030304 developmental biology, 0303 health sciences, Base Sequence, Genetic Variation, medicine.disease, Pedigree, 3. Good health, Europe, Checkpoint Kinase 2, 030220 oncology & carcinogenesis, North America, Female, Oligonucleotide Probes, Protein Kinases, Reports
Abstract: We recently reported that a sequence variant in the cell-cycle–checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer–susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants reported elsewhere, R145W and I157T with breast cancer, we screened 737 BRCA1/2-negative familial breast cancer cases from 605 families, 459 BRCA1/2-positive cases from 335 families, and 723 controls from the United Kingdom, the Netherlands, and North America. All three variants were rare in all groups, and none occurred at significantly elevated frequency in familial breast cancer cases compared with controls. These results indicate that 1100delC may be the only CHEK2 allele that makes an appreciable contribution to breast cancer susceptibility.
Published: 2003

14. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Author: Ju, YS, Tubio, JMC, Mifsud, W, Fu, BY, Davies, HR, Ramakrishna, M, Li, YL, Yates, L, Gundem, G, Tarpey, PS, Behjati, S, Papaemmanuil, E, Martin, S, Fullam, A, Gerstung, M, Nangalia, J, Green, AR, Caldas, C, Borg, A, Tutt, A, Lee, MTM, van 't Veer, LJ (Laura), Tan, BKT, Aparicio, S, Span, PN, Martens, John, Knappskog, S, Vincent-Salomon, A, Borresen-Dale, AL, Eyfjord, JE, Flanagan, AM, Foster, C, Neal, DE, Cooper, C, Eeles, R, Lakhani, SR, Desmedt, C, Thomas, Giju, Richardson, AL, Purdie, CA, Thompson, AM, McDermott, U, Yang, FT, Nik-Zainal, S, Campbell, PJ, Stratton, MR, Ju, YS, Tubio, JMC, Mifsud, W, Fu, BY, Davies, HR, Ramakrishna, M, Li, YL, Yates, L, Gundem, G, Tarpey, PS, Behjati, S, Papaemmanuil, E, Martin, S, Fullam, A, Gerstung, M, Nangalia, J, Green, AR, Caldas, C, Borg, A, Tutt, A, Lee, MTM, van 't Veer, LJ (Laura), Tan, BKT, Aparicio, S, Span, PN, Martens, John, Knappskog, S, Vincent-Salomon, A, Borresen-Dale, AL, Eyfjord, JE, Flanagan, AM, Foster, C, Neal, DE, Cooper, C, Eeles, R, Lakhani, SR, Desmedt, C, Thomas, Giju, Richardson, AL, Purdie, CA, Thompson, AM, McDermott, U, Yang, FT, Nik-Zainal, S, Campbell, PJ, and Stratton, MR
Abstract: Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.
Published: 2015

15. Bayesian refinement of association signals for 14 loci in 3 common diseases

Author: Maller, JB, McVean, G, Byrnes, J, Vukcevic, D, Palin, K, Su, Z, Howson, JMM, Auton, A, Myers, S, Morris, A, Pirinen, M, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Craddock, N, Hurles, M, Ouwehand, W, Parkes, M, Rahman, N, Duncanson, A, Todd, JA, Kwiatkowski, DP, Samani, NJ, Gough, SCL, McCarthy, MI, Deloukas, P, and Donnelly, P
Subjects: endocrine system diseases, Posterior probability, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, FTO gene, Polymorphism, Single Nucleotide, Article, Bayes' theorem, Genetics, Humans, CTLA-4 Antigen, Genetic Predisposition to Disease, Genetic association, Cyclin-Dependent Kinase Inhibitor p15, Homeodomain Proteins, tRNA Methyltransferases, Genes, p16, Proteins, nutritional and metabolic diseases, Bayes Theorem, Cyclin-Dependent Kinase 5, Graves Disease, TRNA Methyltransferases, Diabetes Mellitus, Type 2, Genetic Loci, TCF7L2, Transcription Factor 7-Like 2 Protein, Genome-Wide Association Study, Transcription Factors
Abstract: To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

16. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author: Jostins, Luke, Ripke, Stephan, Weersma, Rinse K., Duerr, Richard H., Mcgovern, Dermot P., Hui, Ken Y., Lee, James C., Philip Schumm, L., Sharma, Yashoda, Anderson, Carl A., Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L., Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Andrews, Jane M., Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A., Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D'Amato, Mauro, De Jong, Dirk, Devaney, Kathy L., Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R., Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Xinli, Hu, Karlsen, Tom H., Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R., Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Regueiro, Miguel, Rotter, Jerome I., Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A., Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kent D., Tremelling, Mark, Verspaget, Hein W., De Vos, Martine, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhao, Hongyu, Silverberg, Mark S., Annese, Vito, Hakonarson, Hakon, Brant, Steven R., Radford Smith, Graham, Mathew, Christopher G., Rioux, John D., Schadt, Eric E., Daly, Mark J., Franke, Andre, Parkes, Miles, Vermeire, Severine, Barrett, Jeffrey C., Cho, Judy H., Barclay, M, Peyrin Biroulet, L, Chamaillard, M, Colombel, Jf, Cottone, M, Croft, A, D'Incà, R, Halfvarson J, Hanigan K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lémann, M, Levine, A, Massey, D, Milla, M, Montgomery, Gw, Ng, Sm, Oikonomou, I, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, Laura, Taylor, Km, Törkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Andrews, Jm, Bampton, Pa, Florin, Th, Gearry, R, Krishnaprasad, K, Lawrance, Ic, Mahy, G, Radford Smith, G, Roberts, Rl, Simms, La, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie AM 3rd, Beck, K, Bernard, Ej, Binion, Dg, Bitton, A, Brant, Sr, Cho, Jh, Cohen, A, Croitoru, K, Daly, Mj, Datta, Lw, Deslandres, C, Duerr, Rh, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, Gr, Haritunians, T, Jobin, G, Katz, S, Lahaie, Rg, Mcgovern, Dp, Nelson, L, Ning, K, Paré, P, Regueiro, Md, Rioux, Jd, Ruggiero, E, Schumm, L, Schwartz, M, Scott, R, Sharma, Y, Silverberg, Ms, Spears, D, Steinhart, A, Stempak, Jm, Swoger, Jm, Tsagarelis, C, Zhang, C, Zhao, H, Aerts, J, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, Sg, Balmforth, Aj, Barnes, C, Barrett, Jc, Barroso, I, Barton, A, Bennett, Aj, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, Oj, Braund, Ps, Bredin, F, Breen, G, Brown, Mj, Bruce, In, Bull, J, Burren, Os, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, Cm, Coffey, Aj, Connell, Jm, Conrad, Df, Cooper, Jd, Dominiczak, Af, Downes, K, Drummond, He, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, Dm, Evans, G, Eyre, S, Farmer, A, Ferrier, In, Flynn, E, Forbes, A, Forty, L, Franklyn, Ja, Frayling, Tm, Freathy, Rm, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon Smith, K, Gray, E, Green, E, Groves, Cj, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, Ga, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, Jm, Hughes, D, Hunt, S, Isaacs, Jd, Jain, M, Jewell, Dp, Johnson, T, Jolley, Jd, Jones, Ir, Jones, La, Kirov, G, Langford, Cf, Lango Allen, H, Lathrop, Gm, Lee, J, Lee, Kl, Lees, C, Lewis, K, Lindgren, Cm, Maisuria Armer, M, Maller, J, Mansfield, J, Marchini, Jl, Martin, P, Massey, Dc, Mcardle, Wl, Mcguffin, P, Mclay, Ke, Mcvean, G, Mentzer, A, Mimmack, Ml, Morgan, Ae, Morris, Ap, Mowat, C, Munroe, Pb, Myers, S, Newman, W, Nimmo, Er, O'Donovan, Mc, Onipinla, A, Ovington, Nr, Owen, Mj, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, Jr, Phillips, A, Plagnol, V, Prescott, Nj, Prokopenko, I, Quail, Ma, Rafelt, S, Rayner, Nw, Reid, Dm, Renwick, A, Ring, Sm, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, Jg, Sanderson, Jd, Sawcer, Sj, Schuilenburg, H, Scott, Ce, Seal, S, Shaw Hawkins, S, Shields, Bm, Simmonds, Mj, Smyth, Dj, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, He, Stirrups, K, Stone, Ma, Strachan, Dp, Su, Z, Symmons, Dp, Thompson, Jr, Thomson, W, Tobin, Md, Travers, Me, Turnbull, C, Vukcevic, D, Wain, Lv, Walker, M, Walker, Nm, Wallace, C, Warren Perry, M, Watkins, Na, Webster, J, Weedon, Mn, Wilson, Ag, Woodburn, M, Wordsworth, Bp, Yau, C, Young, Ah, Zeggini, E, Brown, Ma, Burton, Pr, Caulfield, Mj, Compston, A, Farrall, M, Gough, Sc, Hall, As, Hattersley, At, Hill, Av, Mathew, Cg, Pembrey, M, Satsangi, J, Stratton, Mr, Worthington, J, Hurles, Me, Duncanson, A, Ouwehand, Wh, Parkes, M, Rahman, N, Todd, Ja, Samani, Nj, Kwiatkowski, Dp, Mccarthy, Mi, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, Jm, Bramon, E, Casas, Jp, Corvin, A, Jankowski, J, Markus, Hs, Palmer, Cn, Plomin, R, Rautanen, A, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Genome-wide association study, Disease, SUSCEPTIBILITY, Inflammatory bowel disease, NUMBER, 0302 clinical medicine, Crohn Disease, NETWORK, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Ulcerative colitis, 3. Good health, Colitis, Ulcerative, Genetic Predisposition to Disease, Genome, Human, Haplotypes, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Genome-Wide Association Study, Host-Pathogen Interactions, IRGM, Medical genetics, 030211 gastroenterology & hepatology, EXPRESSION, medicine.medical_specialty, Immunology, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], TUBERCULOSIS, 03 medical and health sciences, Medical research, medicine, Allele, METAANALYSIS, 030304 developmental biology, HYPER-IGE SYNDROME, MUTATIONS, medicine.disease, RISK LOCI, Genetic architecture, digestive system diseases
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
Published: 2012

17. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

Author: Ju, YSE, Alexandrov, LB, Gerstung, M, Martincorena, I, Nik-Zainal, S, Ramakrishna, M, Davies, HR, Papaemmanuil, E, Gundem, G, Shlien, A, Bolli, N, Behjati, S, Tarpey, PS, Nangalia, J, Massie, CE, Butler, AP, Teague, JW, Vassiliou, GS, Green, AR, Du, MQ, Unnikrishnan, A, Pimanda, JE, Teh, BTE, Munshi, N, Greaves, M, Vyas, P, El-Naggar, AK, Santarius, T, Collins, VP, Grundy, R, Taylor, JA, Hayes, DN, Malkin, D, Foster, CS, Warren, AY, Whitaker, HC, Brewer, D, Eeles, R, Cooper, C, Neal, D, Visakorpi, T, Isaacs, WB, Bova, GS, Flanagan, AM, Futreal, PA, Lynch, AG, Chinnery, PF, McDermott, U, Stratton, MR, Campbell, PJ, Ju, YSE, Alexandrov, LB, Gerstung, M, Martincorena, I, Nik-Zainal, S, Ramakrishna, M, Davies, HR, Papaemmanuil, E, Gundem, G, Shlien, A, Bolli, N, Behjati, S, Tarpey, PS, Nangalia, J, Massie, CE, Butler, AP, Teague, JW, Vassiliou, GS, Green, AR, Du, MQ, Unnikrishnan, A, Pimanda, JE, Teh, BTE, Munshi, N, Greaves, M, Vyas, P, El-Naggar, AK, Santarius, T, Collins, VP, Grundy, R, Taylor, JA, Hayes, DN, Malkin, D, Foster, CS, Warren, AY, Whitaker, HC, Brewer, D, Eeles, R, Cooper, C, Neal, D, Visakorpi, T, Isaacs, WB, Bova, GS, Flanagan, AM, Futreal, PA, Lynch, AG, Chinnery, PF, McDermott, U, Stratton, MR, and Campbell, PJ
Abstract: Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
Published: 2014

18. Processed pseudogenes acquired somatically during cancer development

Author: Cooke, SL, Shlien, A, Marshall, J, Pipinikas, CP, Martincorena, I, Tubio, JMC, Li, Y, Menzies, A, Mudie, L, Ramakrishna, M, Yates, L, Davies, H, Bolli, N, Bignell, GR, Tarpey, PS, Behjati, S, Nik-Zainal, S, Papaemmanuil, E, Teixeira, VH, Raine, K, O'Meara, S, Dodoran, MS, Teague, JW, Butler, AP, Iacobuzio-Donahue, C, Santarius, T, Grundy, RG, Malkin, D, Greaves, M, Munshi, N, Flanagan, AM, Bowtell, D, Martin, S, Larsimont, D, Reis-Filho, JS, Boussioutas, A, Taylor, JA, Hayes, DN, Janes, SM, Futreal, PA, Stratton, MR, McDermott, U, Campbell, PJ, Cooke, SL, Shlien, A, Marshall, J, Pipinikas, CP, Martincorena, I, Tubio, JMC, Li, Y, Menzies, A, Mudie, L, Ramakrishna, M, Yates, L, Davies, H, Bolli, N, Bignell, GR, Tarpey, PS, Behjati, S, Nik-Zainal, S, Papaemmanuil, E, Teixeira, VH, Raine, K, O'Meara, S, Dodoran, MS, Teague, JW, Butler, AP, Iacobuzio-Donahue, C, Santarius, T, Grundy, RG, Malkin, D, Greaves, M, Munshi, N, Flanagan, AM, Bowtell, D, Martin, S, Larsimont, D, Reis-Filho, JS, Boussioutas, A, Taylor, JA, Hayes, DN, Janes, SM, Futreal, PA, Stratton, MR, McDermott, U, and Campbell, PJ
Abstract: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
Published: 2014

19. Patterns of somatic mutation in human cancer genomes

Author: Greenman, C, Stephens, P, Smith, R, Dalgliesh, GL, Hunter, C, Bignell, G, Davies, H, Teague, J, Butler, A, Edkins, S, O'Meara, S, Vastrik, I, Schmidt, EE, Avis, T, Barthorpe, S, Bhamra, G, Buck, G, Choudhury, B, Clements, J, Cole, J, Dicks, E, Forbes, S, Gray, K, Halliday, K, Harrison, R, Hills, K, Hinton, J, Jenkinson, A, Jones, D, Menzies, A, Mironenko, T, Perry, J, Raine, K, Richardson, D, Shepherd, R, Small, A, Tofts, C, Varian, J, Webb, T, West, S, Widaa, S, Yates, A, Cahill, DP, Louis, DN, Goldstraw, P, Nicholson, AG, Brasseur, F, Looijenga, LHJ (Leendert), Weber, BL, Chiew, YE, Defazio, A, Greaves, MF, Green, AR, Campbell, P, Birney, E, Easton, DF, Chenevix-Trench, G, Tan, MH, Khoo, SK, Teh, BT, Yuen, ST, Leung, SY, Wooster, R, Futreal, PA, Stratton, MR, and Pathology
Subjects: SDG 3 - Good Health and Well-being
Published: 2007

20. Erratum: Corrigendum: Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Author: Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Luxton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, ICGC Prostate Group, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, and Neal, DE
Subjects: Genetics, Prostate cancer, medicine.anatomical_structure, Phylogenetics, Prostate, ICGC Prostate Group, medicine, 11 Medical And Health Sciences, 06 Biological Sciences, Biology, medicine.disease, Developmental Biology
Published: 2015

21. Mutations in a novel member of the FERM family, FRMD7 cause X-linked idiopathic congenital nystagmus (NYS1)

Author: Tarpey, P, Thomas, S, Sarvananthan, N, Mallya, U, Lisgo, S, Talbot, CJ, Roberts, EO, Awan, M, Surendran, M, McLean, RJ, Reinecke, RD, Langmann, A, Lindner, S, Koch, M, Woodruff, G, Gale, R, Degg, C, Droutsas, K, Asproudis, I, Zubcov, AA, Pieh, C, Veal, CD, Machado, RD, Backhouse, OC, Baumber, L, Jain, S, Constantinescu, CS, Brodsky, MC, Hunter, DG, Hertle, RW, Read, RJ, Edkins, S, O’Meara, S, Parker, A, Stevens, C, Teague, J, Wooster, R, Futreal, PA, Trembath, RC, Stratton, MR, Raymond, FL, and Gottlob, I
Subjects: Male, Chromosomes, Human, X, genetic structures, Eye Movements, Genetic Linkage, Brain, Chromosome Mapping, Gene Expression Regulation, Developmental, Membrane Proteins, eye diseases, Article, Retina, Pedigree, Cytoskeletal Proteins, Genes, X-Linked, Mutation, Humans, Female, Nystagmus, Congenital
Abstract: Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.
Published: 2006

22. The Y deletion gr/gr and susceptibility to testicular germ cell tumor

Author: Nathanson, KL, Kanetsky, PA, Hawes, R, Vaughn, DJ, Letrero, R, Tucker, K, Friedlander, M, Phillips, KA, Hogg, D, Jewett, MAS, Lohynska, R, Daugaard, G, Richard, S, Chompret, A, Bonati-Pellie, C, Heidenreich, A, Olah, E, Geczi, L, Bodrogi, I, Ormiston, WJ, Daly, PA, Oosterhuis, Wolter, Gillis, Ad, Looijenga, LHJ (Leendert), Guilford, P, Fossa, SD, Heimdal, K, Tjulandin, SA, Liubchenko, L, Stoll, H, Weber, W, Huddart, R, Crockford, GP, Forman, D, Oliver, DT, Einhorn, L, Weber, BL, Kramer, J (Judith), McMaster, M, Greene, MH, Pike, M, Cortessis, V, Chen, C (Christopher Li Hsian), Schwartz, SM, Bishop, DT, Easton, DF, Stratton, MR, Rapley, EA, Pathology, and Immunology
Published: 2005

23. Lung cancer: intragenic ERBB2 kinase mutations in tumours

Author: Stephens, P, Hunter, C, Bignell, G, Edkins, S, Davies, H, Teague, J, Stevens, C, O'Meara, S, Smith, R, Barthorpe, A, Blow, M, Brackenbury, L, Butler, A, Clarke, O, Cole, J, Dicks, E, Dike, A, Drozd, A, Edwards, K, Forbes, S, Foster, S, Gray, K, Greenman, C, Halliday, K, Hills, K, Kosmidou, V, Lugg, R, Menzies, A, Perry, J, Petty, R, Raine, K, Ratford, L, Shepherd, R, Small, A, Stephens, Y, Tofts, C, Varian, J, West, S, Widaa, S, Yates, A, Brasseur, F, Cooper, CS, Flanagan, AM, Knowles, M, Leung, S, Louis, DN, Looijenga, LHJ (Leendert), Malkowicz, B, Pierotti, MA, Teh, B, Chenevix-Trench, G, Weber, W, Yuen, ST, Harris, G, Goldstraw, P, Nicholson, AG, Futreal, PA, Wooster, R, Stratton, MR, and Pathology
Subjects: SDG 3 - Good Health and Well-being
Published: 2004

24. The CHEK2*1100delC variant is a genetic modifier in non-BRCA1/BRCA2 breast cancer families

Author: Schutte, Mieke, Meijers-Heijboer, EJ, Klijn, Jan, Wasielewski, M (Marijke), Easton, D, Sodha, N, Rahman, N, Stratton, MR, Medical Oncology, and Clinical Genetics
Subjects: SDG 3 - Good Health and Well-being
Published: 2003

25. Signatures of mutational processes in human cancer

Author: Alexandrov, LB, Nik-Zainal, S, Wedge, DC, Aparicio, SAJR, Behjati, S, Biankin, AV, Bignell, GR, Bolli, N, Borg, A, Borresen-Dale, A-L, Boyault, S, Burkhardt, B, Butler, AP, Caldas, C, Davies, HR, Desmedt, C, Eils, R, Eyfjord, JE, Foekens, JA, Greaves, M, Hosoda, F, Hutter, B, Ilicic, T, Imbeaud, S, Imielinsk, M, Jaeger, N, Jones, DTW, Jones, D, Knappskog, S, Kool, M, Lakhani, SR, Lopez-Otin, C, Martin, S, Munshi, NC, Nakamura, H, Northcott, PA, Pajic, M, Papaemmanuil, E, Paradiso, A, Pearson, JV, Puente, XS, Raine, K, Ramakrishna, M, Richardson, AL, Richter, J, Rosenstiel, P, Schlesner, M, Schumacher, TN, Span, PN, Teague, JW, Totoki, Y, Tutt, ANJ, Valdes-Mas, R, van Buuren, MM, van 't Veer, L, Vincent-Salomon, A, Waddell, N, Yates, LR, Zucman-Rossi, J, Futreal, PA, McDermott, U, Lichter, P, Meyerson, M, Grimmond, SM, Siebert, R, Campo, E, Shibata, T, Pfister, SM, Campbell, PJ, Stratton, MR, Alexandrov, LB, Nik-Zainal, S, Wedge, DC, Aparicio, SAJR, Behjati, S, Biankin, AV, Bignell, GR, Bolli, N, Borg, A, Borresen-Dale, A-L, Boyault, S, Burkhardt, B, Butler, AP, Caldas, C, Davies, HR, Desmedt, C, Eils, R, Eyfjord, JE, Foekens, JA, Greaves, M, Hosoda, F, Hutter, B, Ilicic, T, Imbeaud, S, Imielinsk, M, Jaeger, N, Jones, DTW, Jones, D, Knappskog, S, Kool, M, Lakhani, SR, Lopez-Otin, C, Martin, S, Munshi, NC, Nakamura, H, Northcott, PA, Pajic, M, Papaemmanuil, E, Paradiso, A, Pearson, JV, Puente, XS, Raine, K, Ramakrishna, M, Richardson, AL, Richter, J, Rosenstiel, P, Schlesner, M, Schumacher, TN, Span, PN, Teague, JW, Totoki, Y, Tutt, ANJ, Valdes-Mas, R, van Buuren, MM, van 't Veer, L, Vincent-Salomon, A, Waddell, N, Yates, LR, Zucman-Rossi, J, Futreal, PA, McDermott, U, Lichter, P, Meyerson, M, Grimmond, SM, Siebert, R, Campo, E, Shibata, T, Pfister, SM, Campbell, PJ, and Stratton, MR
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
Published: 2013

26. Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer

Author: Murchison, EP, Schulz-Trieglaff, OB, Ning, Z, Alexandrov, LB, Bauer, MJ, Fu, B, Hims, M, Ding, Z, Ivakhno, S, Stewart, C, Ng, BL, Wong, W, Aken, B, White, S, Alsop, A, Becq, J, Bignell, GR, Cheetham, RK, Cheng, W, Connor, TR, Cox, AJ, Feng, Z-P, Gu, Y, Grocock, RJ, Harris, SR, Khrebtukova, I, Kingsbury, Z, Kowarsky, M, Kreiss, A, Luo, S, Marshall, J, McBride, DJ, Murray, L, Pearse, A-M, Raine, K, Rasolonjatovo, I, Shaw, R, Tedder, P, Tregidgo, C, Vilella, AJ, Wedge, DC, Woods, GM, Gormley, N, Humphray, S, Schroth, G, Smith, G, Hall, K, Searle, SMJ, Carter, NP, Papenfuss, AT, Futreal, PA, Campbell, PJ, Yang, F, Bentley, DR, Evers, DJ, Stratton, MR, Murchison, EP, Schulz-Trieglaff, OB, Ning, Z, Alexandrov, LB, Bauer, MJ, Fu, B, Hims, M, Ding, Z, Ivakhno, S, Stewart, C, Ng, BL, Wong, W, Aken, B, White, S, Alsop, A, Becq, J, Bignell, GR, Cheetham, RK, Cheng, W, Connor, TR, Cox, AJ, Feng, Z-P, Gu, Y, Grocock, RJ, Harris, SR, Khrebtukova, I, Kingsbury, Z, Kowarsky, M, Kreiss, A, Luo, S, Marshall, J, McBride, DJ, Murray, L, Pearse, A-M, Raine, K, Rasolonjatovo, I, Shaw, R, Tedder, P, Tregidgo, C, Vilella, AJ, Wedge, DC, Woods, GM, Gormley, N, Humphray, S, Schroth, G, Smith, G, Hall, K, Searle, SMJ, Carter, NP, Papenfuss, AT, Futreal, PA, Campbell, PJ, Yang, F, Bentley, DR, Evers, DJ, and Stratton, MR
Abstract: The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.
Published: 2012

27. Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes

Author: McBride, DJ, Etemadmoghadam, D, Cooke, SL, Alsop, K, George, J, Butler, A, Cho, J, Galappaththige, D, Greenman, C, Howarth, KD, Lau, KW, Ng, CK, Raine, K, Teague, J, Wedge, DC, Caubit, X, Stratton, MR, Brenton, JD, Campbell, PJ, Futreal, PA, Bowtell, DDL, McBride, DJ, Etemadmoghadam, D, Cooke, SL, Alsop, K, George, J, Butler, A, Cho, J, Galappaththige, D, Greenman, C, Howarth, KD, Lau, KW, Ng, CK, Raine, K, Teague, J, Wedge, DC, Caubit, X, Stratton, MR, Brenton, JD, Campbell, PJ, Futreal, PA, and Bowtell, DDL
Abstract: The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome.
Published: 2012

28. Mutational Processes Molding the Genomes of 21 Breast Cancers

Author: Nik-Zainal, S, Alexandrov, LB, Wedge, DC, van Loo, PF, Greenman, CD, Raine, K, Jones, D, Hinton, J, Marshall, J, Stebbings, LA, Menzies, A, Martin, S, Leung, Esther, Chen, Lina, Leroy, C, Ramakrishna, M, Rance, R, Lau, KW, Mudie, LJ, Varela, I, McBride, DJ, Bignell, GR, Cooke, SL, Shlien, A, Gamble, J, Whitmore, I, Maddison, M, Tarpey, PS, Davies, HR, Papaemmanuil, E, Stephens, PJ, McLaren, S, Butler, AP, Teague, JW, Jonsson, G, Garber, JE, Silver, D, Miron, P, Fatima, A, Boyault, S, Langerod, A, Tutt, A, Martens, John, Aparicio, SAJR, Borg, A, Salomon, AV, Thomas, Giju, Borresen-Dale, AL, Richardson, AL, Neuberger, MS, Futreal, PA, Campbell, PJ, Stratton, MR, Nik-Zainal, S, Alexandrov, LB, Wedge, DC, van Loo, PF, Greenman, CD, Raine, K, Jones, D, Hinton, J, Marshall, J, Stebbings, LA, Menzies, A, Martin, S, Leung, Esther, Chen, Lina, Leroy, C, Ramakrishna, M, Rance, R, Lau, KW, Mudie, LJ, Varela, I, McBride, DJ, Bignell, GR, Cooke, SL, Shlien, A, Gamble, J, Whitmore, I, Maddison, M, Tarpey, PS, Davies, HR, Papaemmanuil, E, Stephens, PJ, McLaren, S, Butler, AP, Teague, JW, Jonsson, G, Garber, JE, Silver, D, Miron, P, Fatima, A, Boyault, S, Langerod, A, Tutt, A, Martens, John, Aparicio, SAJR, Borg, A, Salomon, AV, Thomas, Giju, Borresen-Dale, AL, Richardson, AL, Neuberger, MS, Futreal, PA, Campbell, PJ, and Stratton, MR
Abstract: All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
Published: 2012

29. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers

Author: Ha, Shih, Katherine Nathanson, Seal S, Collins N, Stratton MR, Tr, Rebbeck, and Bl, Weber
Subjects: BRCA2 Protein, Neoplasms, Multiple Primary, Mutation, Genes, BRCA1, Humans, Breast Neoplasms, Female, Middle Aged, Neoplasm Proteins, Transcription Factors
Abstract: Ninety-eight women ascertained from high-risk breast/ovarian cancer clinics with breast cancer reporting at least one other primary cancer in themselves or in a relative with breast cancer were compared with 99 women with breast cancer who reported a family history of breast cancer only. All DNA was screened for coding region mutations in BRCA1 and BRCA2 using heteroduplex analysis, followed by direct sequencing. Our data indicate that 42.9% of families reporting breast and any second nonbreast type of primary cancer in the same individual had a BRCA1 or BRCA2 mutation, as compared with the 12.1% of families reporting breast cancer only (P0.001). Among the 66 women reporting breast cancer and a nonovarian second primary cancer, 15 (22.7%) had mutations in BRCA1 or BRCA2 (P = 0.04). Among the 32 families where ovarian cancer was the second primary cancer, 27 (84.4%) had a mutation in BRCA1 or BRCA2 (P0.001). BRCA1 and BRCA2 mutations were twice as common in the presence of a reported second nonovarian cancer. These data suggest that the presence of multiple primary cancer of any kind may predict for an increased likelihood of finding a BRCA1 or BRCA2 mutation and supports previous studies suggesting that BRCA1 and BRCA2 mutations may be associated with an increased susceptibility to cancers other than breast and ovarian cancer.
Published: 2000

30. Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families

Author: Peelen, T, van der Vliet, MK, Bosch, A, Bignell, G, Vasen, HFA, Klijn, Jan, Meijers-Heijboer, EJ, Stratton, MR, van Ommen, G-JB, Cornelisse, CJ, Devilee, P, Clinical Genetics, and Medical Oncology
Subjects: SDG 3 - Good Health and Well-being
Published: 2000

31. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2

Author: Lakhani, SR, Gusterson, BA, Jacquemier, J, Sloane, JP, Anderson, TJ, van de Vijver, MJ, Venter, D, Freeman, A, Antoniou, A, McGuffog, L, Smyth, E, Steel, CM, Haites, N, Scott, RJ, Goldgar, D, Neuhausen, S, Daly, PA, Ormiston, W, Scherneck, S, Ponder, BAJ, Futreal, PA, Peto, J, Stoppa-Lyonnet, D, Bignon, Y-J, Struewing, JP, Bishop, DT, Klijn, Jan, Devilee, P, Cornelisse, CJ, Lasset, C, Lenoir, G, Barkadottir, RB, Egilsson, V, Hamann, U, Chang-Claude, J, Sobol, H, Weber, B, Easton, DF, Stratton, MR, and Medical Oncology
Subjects: SDG 3 - Good Health and Well-being
Published: 2000

32. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts

Author: Papaemmanuil, E, Cazzola, M, Boultwood, J, Malcovati, L, Vyas, P, Bowen, D, Pellagatti, A, Wainscoat, J, Hellstrom Lindberg, E, GAMBACORTI PASSERINI, C, Godfrey, A, Rapado, I, Cvejic, A, Rance, R, Mcgee, C, Ellis, P, Mudie, L, Stephens, P, Mclaren, S, Massie, C, Tarpey, P, Varela, I, Nik Zainal, S, Davies, H, Shlien, A, Jones, D, Raine, K, Hinton, J, Butler, A, Teague, J, Baxter, E, Score, J, Galli, A, Della Porta, M, Travaglino, E, Groves, M, Tauro, S, Munshi, N, Anderson, K, El Naggar, A, Fischer, A, Mustonen, V, Warren, A, Cross, N, Green, A, Futreal, P, Stratton, M, Campbell, P, Chronic Myeloid Disorders Working Group of the International Cancer Genome, C, Wainscoat, JS, Godfrey, AL, McGee, C, Mudie, LJ, Stephens, PJ, McLaren, S, Massie, CE, Tarpey, PS, Davies, HR, Butler, AP, Teague, JW, Baxter, EJ, Della Porta, MG, Munshi, NC, Anderson, KC, Warren, AJ, Cross, NC, Green, AR, Futreal, PA, Stratton, MR, Campbell, PJ, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, GAMBACORTI PASSERINI, CARLO, Papaemmanuil, E, Cazzola, M, Boultwood, J, Malcovati, L, Vyas, P, Bowen, D, Pellagatti, A, Wainscoat, J, Hellstrom Lindberg, E, GAMBACORTI PASSERINI, C, Godfrey, A, Rapado, I, Cvejic, A, Rance, R, Mcgee, C, Ellis, P, Mudie, L, Stephens, P, Mclaren, S, Massie, C, Tarpey, P, Varela, I, Nik Zainal, S, Davies, H, Shlien, A, Jones, D, Raine, K, Hinton, J, Butler, A, Teague, J, Baxter, E, Score, J, Galli, A, Della Porta, M, Travaglino, E, Groves, M, Tauro, S, Munshi, N, Anderson, K, El Naggar, A, Fischer, A, Mustonen, V, Warren, A, Cross, N, Green, A, Futreal, P, Stratton, M, Campbell, P, Chronic Myeloid Disorders Working Group of the International Cancer Genome, C, Wainscoat, JS, Godfrey, AL, McGee, C, Mudie, LJ, Stephens, PJ, McLaren, S, Massie, CE, Tarpey, PS, Davies, HR, Butler, AP, Teague, JW, Baxter, EJ, Della Porta, MG, Munshi, NC, Anderson, KC, Warren, AJ, Cross, NC, Green, AR, Futreal, PA, Stratton, MR, Campbell, PJ, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, and GAMBACORTI PASSERINI, CARLO
Abstract: BACKGROUND: Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS: We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS: We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes
Published: 2011

33. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author: Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Donnelly, P, Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, and Donnelly, P
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Published: 2010

34. International network of cancer genome projects

Author: Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, Wainwright, BJ, Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, and Wainwright, BJ
Abstract: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Published: 2010

35. Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation

Author: Field, M, primary, Tarpey, P, additional, Boyle, J, additional, Edkins, S, additional, Goodship, J, additional, Luo, Y, additional, Moon, J, additional, Teague, J, additional, Stratton, MR, additional, Futreal, PA, additional, Wooster, R, additional, Raymond, FL, additional, and Turner, G, additional
Published: 2006
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36. Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients

Author: Shayeghi, M, primary, Seal, S, additional, Regan, J, additional, Collins, N, additional, Barfoot, R, additional, Rahman, N, additional, Ashton, A, additional, Moohan, M, additional, Wooster, R, additional, Owen, R, additional, Bliss, JM, additional, Stratton, MR, additional, and Yarnold, J, additional
Published: 1998
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37. A missense mutation in the BRCA2 gene in three siblings with ovarian cancer

Author: Roth, S, primary, Kristo, P, additional, Auranen, A, additional, Shayehgi, M, additional, Seal, S, additional, Collins, N, additional, Barfoot, R, additional, Rahman, N, additional, Klemi, PJ, additional, Grénman, S, additional, Sarantaus, L, additional, Nevanlinna, H, additional, Butzow, R, additional, Ashworth, A, additional, Stratton, MR, additional, and Aaltonen, LA, additional
Published: 1998
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38. Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers

Author: Collins, N, primary, Wooster, R, additional, and Stratton, MR, additional
Published: 1997
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39. Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13

Author: Cleton-Jansen, A-M, primary, Collins, N, additional, Lakhani, SR, additional, Weissenbach, J, additional, Devilee, P, additional, Cornelisse, CJ, additional, and Stratton, MR, additional
Published: 1995
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40. Structural alterations of the RB1 gene in human soft tissue tumours.

Author: Stratton, MR, Williams, S, Fisher, C, Ball, A, Westbury, G, Gusterson, BA, Fletcher, CDM, Knight, JC, Fung, Y-K, and Reeves, BR
Published: 1989
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41. Structure of the met protein and variation of met protein kinase activity among human tumour cell lines.

Author: Tempest, PR, Stratton, MR, Cooper, CS, Tempest, P R, Stratton, M R, and Cooper, C S
Published: 1988
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42. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author: Glodzik, D, Morganella, S, Davies, H, Simpson, PT, Li, Y, Zou, X, Diez-Perez, J, Staaf, J, Alexandrov, LB, Smid, M, Brinkman, AB, Rye, IH, Russnes, H, Raine, K, Purdie, CA, Lakhani, Thompson, AM, Birney, E, Stunnenberg, HG, Van De Vijver, MJ, Martens, JWM, Børresen-Dale, A-L, Richardson, AL, Kong, G, Viari, A, Easton, D, Evan, G, Campbell, PJ, Stratton, MR, and Nik-Zainal, S
Subjects: breast cancer, genetics research, genomics, 3. Good health
Abstract: Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

43. Mutational signatures of ionizing radiation in second malignancies

Author: Behjati, S, Gundem, G, Wedge, DC, Roberts, ND, Tarpey, PS, Cooke, SL, Van Loo, P, Alexandrov, LB, Ramakrishna, M, Davies, H, Nik-Zainal, S, Hardy, C, Latimer, C, Raine, KM, Stebbings, L, Menzies, A, Jones, D, Shepherd, R, Butler, AP, Teague, JW, Jorgensen, M, Khatri, B, Pillay, N, Shlien, A, Futreal, PA, Badie, C, ICGC Prostate Group, McDermott, U, Bova, GS, Richardson, AL, Flanagan, AM, Stratton, MR, and Campbell, PJ
Subjects: Male, Osteosarcoma, Radiation, Ionizing, Mutation, Humans, Prostatic Neoplasms, Breast Neoplasms, Female, Neoplasms, Second Primary, Gene Deletion, Germ-Line Mutation, 3. Good health, DNA Damage
Abstract: Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

44. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Author: Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Lmcton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, Neal, DE, and Grp, ICGCP
Subjects: DNA sequencing, prostate cancer, 3. Good health
Abstract: Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases., This work was funded by Cancer Research UK (grant C5047/A14835), the Dallaglio Foundation and the Wellcome Trust. We also acknowledge support from the Bob Champion Cancer Trust, the Orchid Cancer Appeal, the RoseTrees Trust, the North West Cancer Research Fund, Big C, the King family, the Grand Charity of Freemasons, and the Research Foundation Flanders (FWO). We thank D. Holland from the Infrastructure Management Team and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. We acknowledge the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, supported by the National Institute for Health Research. We acknowledge support from the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant G0500966/75466). We thank the National Institute for Health Research, Hutchison Whampoa Limited and the Human Research Tissue Bank (Addenbrooke's Hospital), the Cancer Research UK Cambridge Research Institute Histopathology, the In-situ Hybridisation Core Facility, the Genomics Core Facility Cambridge and the Cambridge University Hospitals Media Studio.

45. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators

Author: Sa, Gayther, Ka, Foy, Harrington P, Pharoah P, Wd, Dunsmuir, Sm, Edwards, Gillett C, Ardern-Jones A, Dp, Dearnaley, Df, Easton, Ford D, Rj, Shearer, Rs, Kirby, Al, Dowe, Kelly J, Stratton MR, Ba, Ponder, Barnes D, and Rosalind Eeles
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Family Health, Male, DNA Mutational Analysis, Genes, BRCA1, Prostatic Neoplasms, Breast Neoplasms, DNA, Neoplasm, Exons, Middle Aged, Neoplasm Proteins, Pedigree, Haplotypes, Cluster Analysis, Humans, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, Transcription Factors
Abstract: Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one wasor = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

46. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Author: Ju, YS, Tubio, JM, Mifsud, W, Fu, B, Davies, HR, Ramakrishna, M, Li, Y, Yates, L, Gundem, G, Tarpey, PS, Behjati, S, Papaemmanuil, E, Martin, S, Fullam, A, Gerstung, M, ICGC Prostate Cancer Working Group, ICGC Bone Cancer Working Group, ICGC Breast Cancer Working Group, Nangalia, J, Green, AR, Caldas, C, Borg, Å, Tutt, A, Lee, MT, Van't Veer, LJ, Tan, BK, Aparicio, S, Span, PN, Martens, JW, Knappskog, S, Vincent-Salomon, A, Børresen-Dale, AL, Eyfjörd, JE, Flanagan, AM, Foster, C, Neal, DE, Cooper, C, Eeles, R, Lakhani, Desmedt, C, Thomas, G, Richardson, AL, Purdie, CA, Thompson, AM, McDermott, U, Yang, F, Nik-Zainal, S, Campbell, PJ, and Stratton, MR
Subjects: NotStemCellInstitute, 3. Good health
Abstract: Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

47. The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas

Author: Pj, Biggs, Chapman P, Sr, Lakhani, John Burn, and Stratton MR
Subjects: Heterozygote, Polymorphism, Genetic, Skin Neoplasms, Humans, Genes, Tumor Suppressor, Carcinoma, Adenoid Cystic, Chromosomes, Human, Pair 16, Gene Deletion
Abstract: Hereditary cylindromatosis is a rare autosomal dominant disease characterised by the development of multiple benign neoplasms of the skin. We recently localised the gene responsible for this disease (cyld1) to chromosome 16q12-q13 and provided evidence that it is a tumour suppressor gene (Biggs et al., 1995). We have now examined polymorphic markers on every chromosome, some of which are close to known tumour suppressor genes, in 25 tumours from 4 individuals with familial cylindromatosis. No loss of heterozygosity (LOH) was detected other than at loci on chromosome 16q. This observation suggests that the cyld1 gene may be the only tumour suppressor gene implicated in the development of cylindromas. We have also demonstrated LOH using markers on chromosome 16q in 8/14 (57%) sporadic cylindromas, indicating that the cyld1 gene is likely to be involved in the genesis of both familial and sporadic cylindromas.

48. Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings

Author: Rosalind Eeles, Warren W, Knee G, Bartek J, Averill D, Stratton MR, Pr, Blake, Dm, Tait, Dp, Lane, and Df, Easton
Subjects: Base Sequence, Molecular Sequence Data, Neoplasms, Second Primary, DNA, Exons, Middle Aged, Genes, p53, Immunohistochemistry, Pedigree, Neoplastic Syndromes, Hereditary, Humans, Point Mutation, Female, Tumor Suppressor Protein p53
Abstract: We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C--T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

49. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia

Author: St, Yuen, Davies H, Tl, Chan, Jw, Ho, Gr, Bignell, Cox C, Stephens P, Sarah Edkins, Ww, Tsui, As, Chan, Pa, Futreal, Stratton MR, Wooster R, and Sy, Leung

50. Genome-wide association study identifies eight loci associated with blood pressure

Author: Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, and Compston, A
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10−24), CYP1A2 (P = 1 × 10−23), FGF5 (P = 1 × 10−21), SH2B3 (P = 3 × 10−18), MTHFR (P = 2 × 10−13), c10orf107 (P = 1 × 10−9), ZNF652 (P = 5 × 10−9) and PLCD3 (P = 1 × 10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

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