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1. Jarilla–Coffea extract: a natural cosmetic product that improves eyelash and eyebrow growth in women

Author: Alonso MR, Pérez Damonte S, and Anesini C
Subjects: Eyelashes thickness, eyebrows thickness, plant extracts, menopause, adverse effects, cosmetic, Dermatology, RL1-803
Abstract: María Rosario Alonso,1 Silvia Pérez Damonte,2 Claudia Anesini1 1Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Department of Pharmacology, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina; 2CLAIM, José Bonifacio 717 (C1424 CHO) Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina Purpose: A combination of extracts, from two plant species, ie, Coffea arabica and Larrea divaricata (Jarilla) (ECOHAIR®), is being successfully used in Argentina as a cosmetic for hair recovery in androgenic and areata alopecia, and for eyelash and eyebrow growth. The objectives of this prospective study were to evaluate the capacity of Jarilla–Coffea extract gel of improving hair growth in relation to thickness, appearance of new hair, and hair length in comparison with a placebo in premenopausal and postmenopausal volunteers and to identify possible signs of ocular adverse local reactions related to the application of the gel.Volunteers and methods: An open-label, placebo-controlled, prospective study was performed in healthy premenopausal and postmenopausal women during a daily administration period of 2 months (eyebrow growth) and 3 months (eyelash growth). The thickness of hair was determined using a video microscope MedicalScope®. The appearance of new hairs and total area with hair in eyebrow and eyelash length were quantified using a photographic record with Fotofinder® (Germany). The number of volunteers presenting variation in growth of new hair and length were also recorded.Results: The product significantly increased the thickness of eyebrows (20% in 80% women) and eyelashes (19.44% in 100% of women). The gel also increased the appearance of new hairs, total area with hair, and length but there was no statistical difference between treatment and placebo.Conclusion: The gel was capable of improving growth of eyelashes and eyebrows by inducing principally hair thickening without causing local adverse effects in a high percentage of volunteers. Keywords: eyelash thickness, eyebrow thickness, plant extracts, menopause, adverse effects, cosmetic
Published: 2019

2. FGF receptor genes and breast cancer susceptibility: Results from the Breast Cancer Association Consortium

Author: Van 'T Veer, Laura, Wu, Alan, Ashworth, Alan, Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, and Bolla, MK
Abstract: Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify ris
Published: 2014

3. Effectiveness of a Multicomponent Group Psychological Intervention Program in Patients with Inflammatory Bowel Disease: A Randomized Trial

Author: Bernabeu P, van-der Hofstadt C, Rodríguez-Marín J, Gutierrez A, Alonso MR, Zapater P, Jover R, and Sempere L
Subjects: psychological intervention, inflammatory bowel disease, disease activity
Abstract: (1) Background: Stress, anxiety, and depression have been identified as factors that influence the development of inflammatory bowel disease (IBD). The main aim of this study was to test the effectiveness of group multicomponent cognitive-behavioral therapy at reducing stress, anxiety, and depression, and improving quality of life and the clinical course of the disease. (2) Methods: A total of 120 patients were evaluated using the General Perceived Stress Scale, Scale of Stress Perceived by the Disease, the anxiety and depression scale, and quality of life questionnaire for patients with IBD. Disease activity was measured using the Mayo Index for ulcerative colitis and CDAI for Crohn's disease, as well as the number of relapses self-reported by patients. Patients were randomized to receive group multicomponent cognitive-behavioral therapy or treatment as usual. (3) Results: The psychological intervention reduced stress (EAE: 45.7 ± 8.8 vs. 40.6 ± 8.4, p = 0.0001; PSS: 28.0 ± 7.3 vs. 25.1 ± 5.9, p = 0.001) and improved quality of life (164.2 ± 34.3 vs. 176.2 ± 28.0, p = 0.001). An improvement was found in the number of relapses self-reported by patients (0.2 relapses/patient vs. control 0.7 relapses/patient; p = 0.027). No differences were found in disease activity indexes. (4) Conclusions: Psychological therapy was associated with improved stress, quality of life and with a decrease in the number of relapses self-reported by patients. Clinical trial registration number: NCT02614014.
Published: 2021

4. DUNE Far Detector Technical Design Report, Volume I. Introduction to DUNE

Author: Abi, B, Acciarri, R, Acero, MA, Adamov, G, Adams, D, Adinolfi, M, Ahmad, Z, Ahmed, J, Alion, T, Monsalve, SA, Alt, C, Anderson, J, Andreopoulos, C, Andrews, M, Andrianala, F, Andringa, S, Ankowski, A, Antonova, M, Antusch, S, Aranda-Fernandez, A, Ariga, A, Arnold, LO, Arroyave, MA, Asaadi, J, Aurisano, A, Aushev, V, Autiero, D, Azfar, F, Back, H, Back, JJ, Backhouse, C, Baesso, P, Bayby, L, Bajou, R, Balasubramanian, S, Baldi, P, Bambah, B, Barao, F, Barenhoim, G, Barker, G, Barkhouse, W, Barnes, C, Barr, G, Monarca, JB, Barros, N, Barrow, JL, Bashyal, A, Basque, V, Bay, F, Alba, JB, Beacom, JF, Bechetoille, E, Behera, B, Bellantoni, L, Bellettini, G, Bellini, V, Beltramello, O, Belver, D, Benckos, N, Neves, FB, Berger, J, Berkman, S, Bernardini, P, Berner, RM, Berns, H, Bertolucci, S, Betancourt, M, Bezawada, Y, Bhattacharjee, M, Bhuyan, B, Biagi, S, Bian, J, Biassoni, M, Bierv, K, Bilki, B, Bishai, M, Bitadze, A, Blake, A, Siffert, BB, Blaszczyk, F, Blazey, G, Blucher, E, Boissevain, J, Bolognesi, S, Bolton, T, Bonesini, M, Bongrand, M, Bonini, F, Booth, A, Booth, C, Bordoni, S, Borkum, A, Boschi, T, Bostan, N, Bour, P, Boyd, S, Bovden, D, Bracinik, J, Braga, D, Brailsford, D, Brandt, A, Bremer, J, Brew, C, Brianne, E, Brice, SJ, Brizzolari, Bromherg, C, Brooijmans, G, Brooke, J, Bross, A, Brunetti, G, Buchanan, N, Budd, H, Caiulo, D, Calaftura, P, Calcutt, J, Calin, M, Calvez, S, Calvo, E, Camilleri, L, Caminata, A, Campanelli, M, Caratelli, D, Carini, G, Carlus, B, Carniti, P, Terrazas, IC, Carranza, H, Castillo, A, Castromonte, C, Cattadori, C, Cavalier, F, Cavanna, F, Centro, S, Cerati, G, Cervelli, A, Cervera Villanueva, A, Chalifour, M, Chang, C, Chardonnet, E, Chatterjee, A, Chattopadhyay, S, Chaves, J, Chen, H, Chen, M, Chen, Y, Cherdack, D, Chi, C, Childress, S, Chiriacescu, A, Cho, K, Choubey, S, Christensen, A, Christian, D, Christodoulou, G, Church, E, Clarke, P, Coan, TE, Cocco, AG, Coelho, J, Conley, E, Conrad, J, Convery, M, Corwin, L, Cotte, P, Cremaldi, L, Cremonesi, L, Crespo-Anadon, JI, Cristaldo, E, Cross, R, Cuesta, C, Cui, Y, Cussans, D, Dahrowski, M, Da Motta, H, Da Silva Peres, L, David, Q, Davies, GS, Davini, S, Dawson, J, De, K, De Almeida, RM, Debbins, P, De Bonis, I, Decowski, M, De Gouvea, A, De Holanda, PC, Astiz, ILDI, Deistin, A, De Jong, P, Delbart, A, Delepine, D, Delgado, M, Dell'Acqua, A, De Lurgio, P, De Mello Neto, JR, DeMuth, DM, Dennis, S, Densham, C, Deptuch, G, De Roeck, A, De Romeri, V, De Vries, J, Dharmapalan, R, Dias, M, Diaz, F, Diaz, J, Di Domizio, S, Di Giulio, L, Ding, P, Di Noto, L, Distefano, C, Diurba, R, Diwan, M, Djurcic, Z, Dokania, N, Dolinski, M, Domine, L, Douglas, D, Drielsma, F, Duchesneau, D, Duffy, K, Dunne, P, Durkin, T, Duyang, H, Dvornikov, O, Dwyer, D, Dyshkant, A, Eads, M, Edmunds, D, Eisch, J, Emery, S, Ereditato, A, Escobar, C, Escudero Sanchez, L, Evans, JJ, Ewart, E, Ezeribe, AC, Fahey, K, Falcone, A, Farnese, C, Farzan, Y, Felix, J, Fernandez-Martinez, E, Menendez, PF, Ferraro, F, Fields, L, Filkins, A, Filthaut, F, Fitzpatrick, RS, Flanagan, W, Fleming, B, Flight, R, Fowler, J, Fox, W, Franc, J, Francis, K, Franco, D, Freeman, J, Freestone, J, Fried, J, Friedland, A, Fuess, S, Furic, I, Furmanski, AP, Gago, A, Gallagher, H, Gallego-Ros, A, Gallice, N, Galymov, V, Gamberini, E, Gamble, T, Gandhi, R, Gandrajula, R, Gao, S, Garcia-Gamez, D, Garcia-Peris, MA, Gardiner, S, Gastler, D, Ge, G, Gelli, B, Gendotti, A, Gent, S, Ghorbani-Moghaddam, Z, Gibin, D, Gil-Botella, L, Girerd, C, Giri, A, Gnani, D, Gogota, O, Gold, M, Gollapinni, S, Gollwitzer, K, Gomes, RA, Bermeo, LG, Fajardo, LSG, Gonnella, F, Gonzalez-Cuevas, J, Goodman, MC, Goodwin, O, Goswami, S, Gotti, C, Goudzovski, E, Grace, C, Graham, M, Gramellini, E, Gran, R, Granados, E, Grant, A, Grant, C, Gratieri, D, Green, P, Green, S, Greenler, L, Greenwood, M, Greer, J, Griffith, C, Groh, M, Grudzinski, J, Grzelak, K, Gu, W, Guarino, V, Guenette, R, Guglielmi, A, Guo, B, Guthikonda, K, Gutierrez, R, Guzowski, P, Guzzo, MM, Gwon, S, Habig, A, Hackenburg, A, Hadavand, H, Haenni, R, Hahn, A, Haigh, J, Haiston, J, Hamernik, T, Hamilton, P, Han, J, Harder, K, Harris, DA, Hartnell, J, Hasegawa, T, Hatcher, R, Hazen, E, Heavey, A, Heeger, KM, Hennessy, K, Henry, S, Morquecho, VH, Herner, K, Hertel, L, Hesam, AS, Hewes, J, Pichardo, AH, Hill, T, Hillier, SJ, Himmel, A, Hoff, J, Hohl, C, Holin, A, Hoppe, E, Horton-Smith, GA, Hostert, M, Hourlier, A, Howard, B, Howell, R, Huang, J, Hugon, J, Iles, G, Iliescu, AM, Illingworth, R, Ioannisian, A, Itay, R, Izmaylov, A, James, E, Jargowsky, B, Jediny, F, Jesus-Valls, C, Ji, X, Jiang, L, Jimenez, S, Jipa, A, Joglekar, A, Johnson, C, Johnson, R, Jones, B, Jones, S, Jung, C, Junk, T, Jwa, Y, Kabirnezhad, M, Kaboth, A, Kadenko, I, Kamiya, F, Karagiorgi, G, Karcher, A, Karolak, M, Karyotakis, Y, Kasai, S, Kasetti, SP, Kashur, L, Kazaryan, N, Kearns, E, Keener, P, Kelly, KJ, Kemp, E, Ketchum, W, Kettell, S, Kliabibullin, M, Khotjantsev, A, Khvedelidze, A, Kim, D, King, B, Kirby, B, Kirby, M, Klein, J, Koehler, K, Koerner, LW, Kohn, S, Koller, PP, Kordosky, M, Kosc, T, Kose, U, Kostelecky, V, Kothekar, K, Krennrich, F, Kreslo, I, Kudenko, Y, Kudryavtsev, V, Kulagin, S, Kumar, J, Kumar, R, Kuruppu, C, Kus, V, Kutter, T, Lamhert, A, Lande, K, Lane, CE, Lang, K, Langford, T, Lasorak, P, Last, D, Lastoria, C, Laundrie, A, Lawrence, A, Lazanu, I, LaZur, R, Le, T, Learned, J, LeBrun, P, Miotto, GL, Lehnert, R, de Oliveira, ML, Leitner, M, Leyton, M, Li, L, Li, S, Li, T, Li, Y, Liao, H, Lin, C, Lin, S, Lister, A, Littlejohn, BR, Liu, J, Lockwitz, S, Loew, T, Lokajicek, M, Lomidze, I, Long, K, Loo, K, Lorca, D, Lord, T, LoSecco, J, Louis, WC, Luk, K, Luo, X, Lurkin, N, Lux, T, Luzio, VP, MacFarland, D, Machado, A, Machado, P, Macias, C, Macier, J, Maddalena, A, Madigan, P, Magill, S, Mahn, K, Maio, A, Maloney, JA, Mandrioli, G, Maneira, JC, Manenti, L, Manly, S, Mann, A, Manolopoulos, K, Plata, MM, Marchionni, A, Marciano, W, Marfatia, D, Mariani, C, Maricic, J, Marinho, F, Marino, AD, Marshak, M, Marshall, C, Marshall, J, Marteau, J, Martin-Alho, J, Martinez, N, Caicedo, DAM, Martynenko, S, Mason, K, Masthaum, A, Masud, M, Matsuno, S, Matthews, J, Mauger, C, Mauri, N, Mavrokoridis, K, Mazza, R, Mazzacane, A, Mazzucato, E, McCluskey, E, McConkey, N, McFarland, KS, McGrew, C, McNab, A, Mefodiev, A, Mehta, P, Melas, P, Mellinato, V, Mena, O, Mcnary, S, Mendez, H, Menegolli, A, Meng, G, Messier, V, Metcalf, W, Mewes, M, Meyer, H, Miao, T, Michna, G, Miedema, T, Migenda, J, Milincic, R, Miller, W, Mills, J, Milne, C, Mineev, O, Miranda, OG, Miryala, S, Mishra, C, Mishra, S, Mislivec, A, Mladenov, D, Mocioiu, I, Moffat, K, Moggi, N, Mohanta, R, Mohayai, TA, Mokhov, N, Molina, JA, Bueno, LM, Montanari, A, Montanari, C, Montanari, D, Montano Zetina, LM, Moon, J, Mooney, M, Moor, A, Moreno, D, Morgan, B, Morris, C, Mossey, C, Motuk, E, Moura, CA, Mousseau, J, Mu, W, Mualem, L, Mueller, J, Muether, M, Mufson, S, Muheim, F, Muir, A, Mulhearn, M, Muramatsu, H, Murphy, S, Musser, J, Nachtman, J, Nagu, S, Nalbandyan, M, Nandakumar, R, Naples, D, Narita, S, Navas-Nicolas, D, Nayak, N, Nebot-Guinot, M, Necib, L, Negishi, K, Nelson, JK, Nesbit, J, Nessi, M, Newbold, D, Newcomer, M, Newhart, D, Nichol, R, Niner, E, Nishimura, K, Norman, A, Northrop, R, Novella, P, Nowak, JA, Oberling, M, Del Campo, AO, Olivier, A, Onel, Y, Onishchuk, Y, Ott, J, Pagani, L, Pakvasa, S, Palamara, O, Palestini, S, Paley, JM, Pallavicini, M, Palomares, C, Pantic, E, Paolone, V, Papadimitriou, V, Papaleo, R, Papanestis, A, Paramesvaran, S, Parke, S, Parsa, Z, Parvu, M, Pascoli, S, Pasqualini, L, Pasternak, J, Pater, J, Patrick, C, Patrizii, L, Patterson, RB, Patton, S, Patzak, T, Paudel, A, Paulos, B, Paulucci, L, Pavlovic, Z, Pawloski, G, Payne, D, Pec, V, Peeters, SJ, Penichot, Y, Pennacchio, E, Penzo, A, Peres, OL, Perry, J, Pershey, D, Pessina, G, Petrillo, G, Petta, C, Petti, R, Piastra, F, Pickering, L, Pietropaolo, F, Pillows, J, Plunkett, R, Poling, R, Pons, X, Poonthottathil, N, Pordes, S, Potekhin, M, Potenza, R, Potukuchi, BV, Pozimski, J, Pozzato, M, Prakash, S, Prakash, T, Prince, S, Prior, G, Pugnere, D, Qi, K, Qian, X, Raaf, J, Raboanary, R, Radeka, V, Rademacker, J, Radics, B, Rafique, A, Raguzin, E, Rai, M, Rajarialisoa, M, Rakhno, I, Rakotondramanana, H, Rakotondravollitra, L, Ramachers, Y, Rameika, R, Delgado, VR, Ramson, B, Rappoldi, A, Raselli, G, Ratoff, P, Ravat, S, Razafinime, H, Real, J, Rebel, B, Redondo, D, Reggiani-Guzzo, M, Rehak, T, Reichenbacher, J, Reitzner, SD, Renshaw, A, Rescia, S, Resnati, F, Reynolds, A, Riccobene, G, Rice, LC, Rielage, K, Rigaut, Y, Rivera, D, Rochester, L, Roda, M, Rodrigues, P, Alonso, MR, Rondon, JR, Roeth, A, Rogers, H, Rosauro-Alcaraz, S, Rossella, M, Rout, J, Roy, S, Rubbia, A, Rubbia, C, Russell, B, Russell, J, Ruterbories, D, Saakyan, R, Sacerdoti, S, Safford, T, Sahu, N, Sala, P, Samios, N, Sanchez, M, Sanders, DA, Sankey, D, Santana, S, Santos-Maldonado, M, Saoulidou, N, Sapienza, P, Sarasty, C, Sarcevic, I, Savage, G, Savinov, V, Scaramelli, A, Scarff, A, Scarpelli, A, Schaffer, T, Schellman, H, Schlabach, P, Schmitz, D, Scholberg, K, Schukraft, A, Segreto, E, Sensenig, J, Seong, I, Sergi, A, Sergiampietri, F, Sgalaberna, D, Shaevitz, M, Shafaq, S, Shamma, M, Sharma, HR, Sharma, R, Shaw, T, Shepherd-Themistocleous, C, Shin, S, Shooltz, D, Shrock, R, Simard, L, Simos, N, Sinclair, J, Sinev, G, Singh, J, Singh, V, Sipos, R, Sippach, F, Sirri, G, Sitraka, A, Siyeon, K, Smargianaki, D, Smith, A, Smith, E, Smith, P, Smolik, J, Smy, M, Snopok, P, Nunes, MS, Sobel, H, Soderberg, M, Salinas, CJS, Soldner-Remhold, S, Solomey, N, Solovov, V, Sondheim, WE, Sorel, M, Soto-Oton, J, Sousa, A, Soustruznik, K, Spagliardi, F, Spanu, M, Spitz, J, Spooner, NJ, Spurgeon, K, Staley, R, Stancari, M, Stanco, L, Steiner, H, Stewart, J, Stillwell, B, Stock, J, Stocker, F, Stokes, T, Strait, M, Strauss, T, Strianov, S, Stuart, A, Summers, D, Surdo, A, Susic, V, Suter, L, Sutera, C, Svoboda, R, Szczerbinska, B, Szelc, A, Talaga, R, Tanaka, H, Oregui, BT, Tapper, A, Tariq, S, Tatar, E, Tayloe, R, Teklu, A, Tenti, M, Terao, K, Ternes, CA, Terranova, F, Testera, G, Thea, A, Thompson, JL, Thorn, C, Timm, S, Tonazzo, A, Torti, M, Tortola, M, Tortorici, F, Totani, D, Toups, M, Touramanis, C, Trevor, J, Trzaska, W, Tsai, Y, Tsamalaidze, Z, Tsang, K, Tsverava, N, Tufanli, S, Tull, C, Tyley, E, Tzanov, V, Uchida, VA, Urheim, J, Usher, T, Vagins, V, Vahle, P, Valdiviesso, G, Valencia, E, Vallari, Z, Valle, JW, Vallecorsa, S, Van Berg, R, Van de Water, RG, Vanegas Forero, D, Varanini, F, Vargas, D, Varner, G, Vasel, J, Vasseur, G, Vaziri, K, Ventura, S, Verdugo, A, Vergani, S, Vermeulen, MA, Verzocchi, M, Vieira de Souza, H, Vignoli, C, Vilela, C, Viren, B, Vrba, T, Wachala, T, Waldron, AV, Wallbank, M, Wang, H, Wang, J, Wang, Y, Warburton, K, Warner, D, Wascko, M, Waters, D, Watson, A, Weatherly, P, Weber, A, Weber, M, Wei, H, Weinstein, A, Wenman, D, Wetstein, M, While, MR, White, A, Whitehead, LH, Whittington, D, Wilking, MJ, Wilkinson, C, Williams, Z, Wilson, F, Wilson, RJ, Wolcott, J, Wongjirad, T, Wood, K, Wood, L, Worcester, E, Worcester, M, Wret, C, Wu, W, Xiao, Y, Yang, G, Yang, T, Yershov, N, Yonehara, K, Young, T, Yu, B, Yu, J, Zalesak, J, Zambelli, L, Zamorano, B, Zani, A, Zazueta, L, Zeller, G, Zennamo, J, Zeug, K, Zhang, C, Zhao, M, Zhivun, E, Zhu, G, Zimmerman, ED, Zito, M, Zuccilelli, S, Zuklin, J, Zuishi, V, Zwaska, R, and Collaboration, DUNE
Subjects: Physics::Instrumentation and Detectors, High Energy Physics::Experiment
Abstract: The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. This TDR is intended to justify the technical choices for the far detector that flow down from the high-level physics goals through requirements at all levels of the Project. Volume I contains an executive summary that introduces the DUNE science program, the far detector and the strategy for its modular designs, and the organization and management of the Project. The remainder of Volume I provides more detail on the science program that drives the choice of detector technologies and on the technologies themselves. It also introduces the designs for the DUNE near detector and the DUNE computing model, for which DUNE is planning design reports. Volume II of this TDR describes DUNE's physics program in detail. Volume III describes the technical coordination required for the far detector design, construction, installation, and integration, and its organizational structure. Volume IV describes the single-phase far detector technology. A planned Volume V will describe the dual-phase technology.
Published: 2020

5. Executive summary

Author: Abi, B, Acciarri, R, Acero, MA, Adamov, G, Adams, D, Adinolfi, M, Ahmad, Z, Ahmed, J, Alion, T, Monsalve, SA, Alt, C, Anderson, J, Andreopoulos, C, Andrews, M, Andrianala, F, Andringa, S, Ankowski, A, Antonova, M, Antusch, S, Aranda-Fernandez, A, Ariga, A, Arnold, LO, Arroyave, MA, Asaadi, J, Aurisano, A, Aushev, V, Autiero, D, Azfar, F, Back, H, Back, JJ, Backhouse, C, Baesso, P, Bayby, L, Bajou, R, Balasubramanian, S, Baldi, P, Bambah, B, Barao, F, Barenhoim, G, Barker, G, Barkhouse, W, Barnes, C, Barr, G, Monarca, JB, Barros, N, Barrow, JL, Bashyal, A, Basque, V, Bay, F, Alba, JB, Beacom, JF, Bechetoille, E, Behera, B, Bellantoni, L, Bellettini, G, Bellini, V, Beltramello, O, Belver, D, Benckos, N, Neves, FB, Berger, J, Berkman, S, Bernardini, P, Berner, RM, Berns, H, Bertolucci, S, Betancourt, M, Bezawada, Y, Bhattacharjee, M, Bhuyan, B, Biagi, S, Bian, J, Biassoni, M, Bierv, K, Bilki, B, Bishai, M, Bitadze, A, Blake, A, Siffert, BB, Blaszczyk, F, Blazey, G, Blucher, E, Boissevain, J, Bolognesi, S, Bolton, T, Bonesini, M, Bongrand, M, Bonini, F, Booth, A, Booth, C, Bordoni, S, Borkum, A, Boschi, T, Bostan, N, Bour, P, Boyd, S, Bovden, D, Bracinik, J, Braga, D, Brailsford, D, Brandt, A, Bremer, J, Brew, C, Brianne, E, Brice, SJ, Brizzolari, Bromherg, C, Brooijmans, G, Brooke, J, Bross, A, Brunetti, G, Buchanan, N, Budd, H, Caiulo, D, Calaftura, P, Calcutt, J, Calin, M, Calvez, S, Calvo, E, Camilleri, L, Caminata, A, Campanelli, M, Caratelli, D, Carini, G, Carlus, B, Carniti, P, Terrazas, IC, Carranza, H, Castillo, A, Castromonte, C, Cattadori, C, Cavalier, F, Cavanna, F, Centro, S, Cerati, G, Cervelli, A, Cervera Villanueva, A, Chalifour, M, Chang, C, Chardonnet, E, Chatterjee, A, Chattopadhyay, S, Chaves, J, Chen, H, Chen, M, Chen, Y, Cherdack, D, Chi, C, Childress, S, Chiriacescu, A, Cho, K, Choubey, S, Christensen, A, Christian, D, Christodoulou, G, Church, E, Clarke, P, Coan, TE, Cocco, AG, Coelho, J, Conley, E, Conrad, J, Convery, M, Corwin, L, Cotte, P, Cremaldi, L, Cremonesi, L, Crespo-Anadon, JI, Cristaldo, E, Cross, R, Cuesta, C, Cui, Y, Cussans, D, Dahrowski, M, Da Motta, H, Da Silva Peres, L, David, Q, Davies, GS, Davini, S, Dawson, J, De, K, De Almeida, RM, Debbins, P, De Bonis, I, Decowski, M, De Gouvea, A, De Holanda, PC, Astiz, ILDI, Deistin, A, De Jong, P, Delbart, A, Delepine, D, Delgado, M, Dell'Acqua, A, De Lurgio, P, De Mello Neto, JR, DeMuth, DM, Dennis, S, Densham, C, Deptuch, G, De Roeck, A, De Romeri, V, De Vries, J, Dharmapalan, R, Dias, M, Diaz, F, Diaz, J, Di Domizio, S, Di Giulio, L, Ding, P, Di Noto, L, Distefano, C, Diurba, R, Diwan, M, Djurcic, Z, Dokania, N, Dolinski, M, Domine, L, Douglas, D, Drielsma, F, Duchesneau, D, Duffy, K, Dunne, P, Durkin, T, Duyang, H, Dvornikov, O, Dwyer, D, Dyshkant, A, Eads, M, Edmunds, D, Eisch, J, Emery, S, Ereditato, A, Escobar, C, Escudero Sanchez, L, Evans, JJ, Ewart, E, Ezeribe, AC, Fahey, K, Falcone, A, Farnese, C, Farzan, Y, Felix, J, Fernandez-Martinez, E, Menendez, PF, Ferraro, F, Fields, L, Filkins, A, Filthaut, F, Fitzpatrick, RS, Flanagan, W, Fleming, B, Flight, R, Fowler, J, Fox, W, Franc, J, Francis, K, Franco, D, Freeman, J, Freestone, J, Fried, J, Friedland, A, Fuess, S, Furic, I, Furmanski, AP, Gago, A, Gallagher, H, Gallego-Ros, A, Gallice, N, Galymov, V, Gamberini, E, Gamble, T, Gandhi, R, Gandrajula, R, Gao, S, Garcia-Gamez, D, Garcia-Peris, MA, Gardiner, S, Gastler, D, Ge, G, Gelli, B, Gendotti, A, Gent, S, Ghorbani-Moghaddam, Z, Gibin, D, Gil-Botella, L, Girerd, C, Giri, A, Gnani, D, Gogota, O, Gold, M, Gollapinni, S, Gollwitzer, K, Gomes, RA, Bermeo, LG, Fajardo, LSG, Gonnella, F, Gonzalez-Cuevas, J, Goodman, MC, Goodwin, O, Goswami, S, Gotti, C, Goudzovski, E, Grace, C, Graham, M, Gramellini, E, Gran, R, Granados, E, Grant, A, Grant, C, Gratieri, D, Green, P, Green, S, Greenler, L, Greenwood, M, Greer, J, Griffith, C, Groh, M, Grudzinski, J, Grzelak, K, Gu, W, Guarino, V, Guenette, R, Guglielmi, A, Guo, B, Guthikonda, K, Gutierrez, R, Guzowski, P, Guzzo, MM, Gwon, S, Habig, A, Hackenburg, A, Hadavand, H, Haenni, R, Hahn, A, Haigh, J, Haiston, J, Hamernik, T, Hamilton, P, Han, J, Harder, K, Harris, DA, Hartnell, J, Hasegawa, T, Hatcher, R, Hazen, E, Heavey, A, Heeger, KM, Hennessy, K, Henry, S, Morquecho, VH, Herner, K, Hertel, L, Hesam, AS, Hewes, J, Pichardo, AH, Hill, T, Hillier, SJ, Himmel, A, Hoff, J, Hohl, C, Holin, A, Hoppe, E, Horton-Smith, GA, Hostert, M, Hourlier, A, Howard, B, Howell, R, Huang, J, Hugon, J, Iles, G, Iliescu, AM, Illingworth, R, Ioannisian, A, Itay, R, Izmaylov, A, James, E, Jargowsky, B, Jediny, F, Jesus-Valls, C, Ji, X, Jiang, L, Jimenez, S, Jipa, A, Joglekar, A, Johnson, C, Johnson, R, Jones, B, Jones, S, Jung, C, Junk, T, Jwa, Y, Kabirnezhad, M, Kaboth, A, Kadenko, I, Kamiya, F, Karagiorgi, G, Karcher, A, Karolak, M, Karyotakis, Y, Kasai, S, Kasetti, SP, Kashur, L, Kazaryan, N, Kearns, E, Keener, P, Kelly, KJ, Kemp, E, Ketchum, W, Kettell, S, Kliabibullin, M, Khotjantsev, A, Khvedelidze, A, Kim, D, King, B, Kirby, B, Kirby, M, Klein, J, Koehler, K, Koerner, LW, Kohn, S, Koller, PP, Kordosky, M, Kosc, T, Kose, U, Kostelecky, V, Kothekar, K, Krennrich, F, Kreslo, I, Kudenko, Y, Kudryavtsev, V, Kulagin, S, Kumar, J, Kumar, R, Kuruppu, C, Kus, V, Kutter, T, Lamhert, A, Lande, K, Lane, CE, Lang, K, Langford, T, Lasorak, P, Last, D, Lastoria, C, Laundrie, A, Lawrence, A, Lazanu, I, LaZur, R, Le, T, Learned, J, LeBrun, P, Miotto, GL, Lehnert, R, De Oliveira, ML, Leitner, M, Leyton, M, Li, L, Li, S, Li, T, Li, Y, Liao, H, Lin, C, Lin, S, Lister, A, Littlejohn, BR, Liu, J, Lockwitz, S, Loew, T, Lokajicek, M, Lomidze, I, Long, K, Loo, K, Lorca, D, Lord, T, LoSecco, J, Louis, WC, Luk, K, Luo, X, Lurkin, N, Lux, T, Luzio, VP, MacFarland, D, Machado, A, Machado, P, Macias, C, Macier, J, Maddalena, A, Madigan, P, Magill, S, Mahn, K, Maio, A, Maloney, JA, Mandrioli, G, Maneira, JC, Manenti, L, Manly, S, Mann, A, Manolopoulos, K, Plata, MM, Marchionni, A, Marciano, W, Marfatia, D, Mariani, C, Maricic, J, Marinho, F, Marino, AD, Marshak, M, Marshall, C, Marshall, J, Marteau, J, Martin-Alho, J, Martinez, N, Caicedo, DAM, Martynenko, S, Mason, K, Masthaum, A, Masud, M, Matsuno, S, Matthews, J, Mauger, C, Mauri, N, Mavrokoridis, K, Mazza, R, Mazzacane, A, Mazzucato, E, McCluskey, E, McConkey, N, McFarland, KS, McGrew, C, McNab, A, Mefodiev, A, Mehta, P, Melas, P, Mellinato, V, Mena, O, Mcnary, S, Mendez, H, Menegolli, A, Meng, G, Messier, V, Metcalf, W, Mewes, M, Meyer, H, Miao, T, Michna, G, Miedema, T, Migenda, J, Milincic, R, Miller, W, Mills, J, Milne, C, Mineev, O, Miranda, OG, Miryala, S, Mishra, C, Mishra, S, Mislivec, A, Mladenov, D, Mocioiu, I, Moffat, K, Moggi, N, Mohanta, R, Mohayai, TA, Mokhov, N, Molina, JA, Bueno, LM, Montanari, A, Montanari, C, Montanari, D, Montano Zetina, LM, Moon, J, Mooney, M, Moor, A, Moreno, D, Morgan, B, Morris, C, Mossey, C, Motuk, E, Moura, CA, Mousseau, J, Mu, W, Mualem, L, Mueller, J, Muether, M, Mufson, S, Muheim, F, Muir, A, Mulhearn, M, Muramatsu, H, Murphy, S, Musser, J, Nachtman, J, Nagu, S, Nalbandyan, M, Nandakumar, R, Naples, D, Narita, S, Navas-Nicolas, D, Nayak, N, Nebot-Guinot, M, Necib, L, Negishi, K, Nelson, JK, Nesbit, J, Nessi, M, Newbold, D, Newcomer, M, Newhart, D, Nichol, R, Niner, E, Nishimura, K, Norman, A, Northrop, R, Novella, P, Nowak, JA, Oberling, M, Del Campo, AO, Olivier, A, Onel, Y, Onishchuk, Y, Ott, J, Pagani, L, Pakvasa, S, Palamara, O, Palestini, S, Paley, JM, Pallavicini, M, Palomares, C, Pantic, E, Paolone, V, Papadimitriou, V, Papaleo, R, Papanestis, A, Paramesvaran, S, Parke, S, Parsa, Z, Parvu, M, Pascoli, S, Pasqualini, L, Pasternak, J, Pater, J, Patrick, C, Patrizii, L, Patterson, RB, Patton, S, Patzak, T, Paudel, A, Paulos, B, Paulucci, L, Pavlovic, Z, Pawloski, G, Payne, D, Pec, V, Peeters, SJ, Penichot, Y, Pennacchio, E, Penzo, A, Peres, OL, Perry, J, Pershey, D, Pessina, G, Petrillo, G, Petta, C, Petti, R, Piastra, F, Pickering, L, Pietropaolo, F, Pillows, J, Plunkett, R, Poling, R, Pons, X, Poonthottathil, N, Pordes, S, Potekhin, M, Potenza, R, Potukuchi, BV, Pozimski, J, Pozzato, M, Prakash, S, Prakash, T, Prince, S, Prior, G, Pugnere, D, Qi, K, Qian, X, Raaf, J, Raboanary, R, Radeka, V, Rademacker, J, Radics, B, Rafique, A, Raguzin, E, Rai, M, Rajarialisoa, M, Rakhno, I, Rakotondramanana, H, Rakotondravollitra, L, Ramachers, Y, Rameika, R, Delgado, VR, Ramson, B, Rappoldi, A, Raselli, G, Ratoff, P, Ravat, S, Razafinime, H, Real, J, Rebel, B, Redondo, D, Reggiani-Guzzo, M, Rehak, T, Reichenbacher, J, Reitzner, SD, Renshaw, A, Rescia, S, Resnati, F, Reynolds, A, Riccobene, G, Rice, LC, Rielage, K, Rigaut, Y, Rivera, D, Rochester, L, Roda, M, Rodrigues, P, Alonso, MR, Rondon, JR, Roeth, A, Rogers, H, Rosauro-Alcaraz, S, Rossella, M, Rout, J, Roy, S, Rubbia, A, Rubbia, C, Russell, B, Russell, J, Ruterbories, D, Saakyan, R, Sacerdoti, S, Safford, T, Sahu, N, Sala, P, Samios, N, Sanchez, M, Sanders, DA, Sankey, D, Santana, S, Santos-Maldonado, M, Saoulidou, N, Sapienza, P, Sarasty, C, Sarcevic, I, Savage, G, Savinov, V, Scaramelli, A, Scarff, A, Scarpelli, A, Schaffer, T, Schellman, H, Schlabach, P, Schmitz, D, Scholberg, K, Schukraft, A, Segreto, E, Sensenig, J, Seong, I, Sergi, A, Sergiampietri, F, Sgalaberna, D, Shaevitz, M, Shafaq, S, Shamma, M, Sharma, HR, Sharma, R, Shaw, T, Shepherd-Themistocleous, C, Shin, S, Shooltz, D, Shrock, R, Simard, L, Simos, N, Sinclair, J, Sinev, G, Singh, J, Singh, V, Sipos, R, Sippach, F, Sirri, G, Sitraka, A, Siyeon, K, Smargianaki, D, Smith, A, Smith, E, Smith, P, Smolik, J, Smy, M, Snopok, P, Nunes, MS, Sobel, H, Soderberg, M, Salinas, CJS, Soldner-Remhold, S, Solomey, N, Solovov, V, Sondheim, WE, Sorel, M, Soto-Oton, J, Sousa, A, Soustruznik, K, Spagliardi, F, Spanu, M, Spitz, J, Spooner, NJ, Spurgeon, K, Staley, R, Stancari, M, Stanco, L, Steiner, H, Stewart, J, Stillwell, B, Stock, J, Stocker, F, Stokes, T, Strait, M, Strauss, T, Strianov, S, Stuart, A, Summers, D, Surdo, A, Susic, V, Suter, L, Sutera, C, Svoboda, R, Szczerbinska, B, Szelc, A, Talaga, R, Tanaka, H, Oregui, BT, Tapper, A, Tariq, S, Tatar, E, Tayloe, R, Teklu, A, Tenti, M, Terao, K, Ternes, CA, Terranova, F, Testera, G, Thea, A, Thompson, JL, Thorn, C, Timm, S, Tonazzo, A, Torti, M, Tortola, M, Tortorici, F, Totani, D, Toups, M, Touramanis, C, Trevor, J, Trzaska, W, Tsai, Y, Tsamalaidze, Z, Tsang, K, Tsverava, N, Tufanli, S, Tull, C, Tyley, E, Tzanov, V, Uchida, VA, Urheim, J, Usher, T, Vagins, V, Vahle, P, Valdiviesso, G, Valencia, E, Vallari, Z, Valle, JW, Vallecorsa, S, Van Berg, R, Van de Water, RG, Vanegas Forero, D, Varanini, F, Vargas, D, Varner, G, Vasel, J, Vasseur, G, Vaziri, K, Ventura, S, Verdugo, A, Vergani, S, Vermeulen, MA, Verzocchi, M, Vieira de Souza, H, Vignoli, C, Vilela, C, Viren, B, Vrba, T, Wachala, T, Waldron, AV, Wallbank, M, Wang, H, Wang, J, Wang, Y, Warburton, K, Warner, D, Wascko, M, Waters, D, Watson, A, Weatherly, P, Weber, A, Weber, M, Wei, H, Weinstein, A, Wenman, D, Wetstein, M, While, MR, White, A, Whitehead, LH, Whittington, D, Wilking, MJ, Wilkinson, C, Williams, Z, Wilson, F, Wilson, RJ, Wolcott, J, Wongjirad, T, Wood, K, Wood, L, Worcester, E, Worcester, M, Wret, C, Wu, W, Xiao, Y, Yang, G, Yang, T, Yershov, N, Yonehara, K, Young, T, Yu, B, Yu, J, Zalesak, J, Zambelli, L, Zamorano, B, Zani, A, Zazueta, L, Zeller, G, Zennamo, J, Zeug, K, Zhang, C, Zhao, M, Zhivun, E, Zhu, G, Zimmerman, ED, Zito, M, Zuccilelli, S, Zuklin, J, Zuishi, V, Zwaska, R, and Science and Technology Facilities Council (STFC)
Subjects: Technology, Science & Technology, 02 Physical Sciences, Physics::Instrumentation and Detectors, NEUTRINO BURST, PERFORMANCE, Nuclear & Particles Physics, 09 Engineering, PHYSICS, ALICE, LIQUID ARGON, OSCILLATIONS, SCATTERING, High Energy Physics::Experiment, Instruments & Instrumentation
Abstract: The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. This TDR is intended to justify the technical choices for the far detector that flow down from the high-level physics goals through requirements at all levels of the Project. Volume I contains an executive summary that introduces the DUNE science program, the far detector and the strategy for its modular designs, and the organization and management of the Project. The remainder of Volume I provides more detail on the science program that drives the choice of detector technologies and on the technologies themselves. It also introduces the designs for the DUNE near detector and the DUNE computing model, for which DUNE is planning design reports. Volume II of this TDR describes DUNE's physics program in detail. Volume III describes the technical coordination required for the far detector design, construction, installation, and integration, and its organizational structure. Volume IV describes the single-phase far detector technology. A planned Volume V will describe the dual-phase technology.
Published: 2020

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

Author: Fachal, L, Aschard, H, Beesley, J, Barnes, DR, Allen, J, Kar, S, Pooley, KA, Dennis, J, Michailidou, K, Turman, C, Soucy, P, Lemaçon, A, Lush, M, Tyrer, JP, Ghoussaini, M, Marjaneh, MM, Jiang, X, Agata, S, Aittomäki, K, Alonso, MR, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Auber, B, Auer, PL, Azzollini, J, Balmaña, J, Barkardottir, RB, Barrowdale, D, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Białkowska, K, Blanco, AM, Blomqvist, C, Blot, W, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Bosse, K, Brauch, H, Brenner, H, Briceno, I, Brock, IW, Brooks-Wilson, A, Brüning, T, Burwinkel, B, Buys, SS, Cai, Q, Caldés, T, Caligo, MA, Camp, NJ, Campbell, I, Canzian, F, Carroll, JS, Carter, BD, Castelao, JE, Chiquette, J, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Mari, V, Berthet, P, Castera, L, Vaur, D, Lallaoui, H, Bignon, YJ, Uhrhammer, N, Bonadona, V, Lasset, C, Révillion, F, Vennin, P, Muller, D, Gomes, DM, Ingster, O, Coupier, I, Pujol, P, Collonge-Rame, MA, Mortemousque, I, Bera, O, Rose, M, Baurand, A, Bertolone, G, Faivre, L, Dreyfus, H, Leroux, D, Venat-Bouvet, L, Bézieau, S, Delnatte, C, Chiesa, J, Gilbert-Dussardier, B, Gesta, P, and Prieur, FP
Subjects: Quantitative Trait Loci, ABCTB Investigators, Breast Neoplasms, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, Medical and Health Sciences, Linkage Disequilibrium, GEMO Study Collaborators, Risk Factors, Breast Cancer, Biomarkers, Tumor, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Aetiology, Polymorphism, EMBRACE Collaborators, HEBON Investigators, Cancer, Tumor, Nucleic Acid, Prevention, Human Genome, Chromosome Mapping, Bayes Theorem, Single Nucleotide, Biological Sciences, Female, KConFab Investigators, Regulatory Sequences, Biomarkers, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Published: 2020

7. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author: Milne, R, Burwinkel, B, Michailidou, K, Arias-Perez, J, Zamora, M, Menéndez-Rodríguez, P, Hardisson, D, Mendiola, M, González-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q, Bolla, M, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y, Brauch, H, Hamann, U, Andrulis, I, Knight, J, Glendon, G, and Tchatchou, S
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Published: 2016

8. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Author: Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, Dunning, AM, Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, and Dunning, AM
Abstract: Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Published: 2016

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

Author: Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Dork, T, Claes, KBM, Reis, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, RX, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruning, T, Ko, YD, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Spurdle, AB, Wauters, Erwin, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, Maartje, Martens, John, Collee, Margriet, Tilanus - Linthorst, Madeleine, Hall, P, Li, JM, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Rudiger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, KT, Stanford, J L, Blot, WJ, Thibodeau, S, Schaid, D J, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J (Judy), Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, A A, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A (Andreas), Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, XF, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, XO, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, HY, Permuth, J B, Sellers, TA, Chen, Y A, Tsai, YY, Chen, ZH, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, HL, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, Milne, RL, Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Dork, T, Claes, KBM, Reis, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, RX, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruning, T, Ko, YD, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Spurdle, AB, Wauters, Erwin, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, Maartje, Martens, John, Collee, Margriet, Tilanus - Linthorst, Madeleine, Hall, P, Li, JM, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Rudiger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, KT, Stanford, J L, Blot, WJ, Thibodeau, S, Schaid, D J, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J (Judy), Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, A A, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A (Andreas), Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, XF, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, XO, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, HY, Permuth, J B, Sellers, TA, Chen, Y A, Tsai, YY, Chen, ZH, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, HL, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, and Milne, RL
Abstract: Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

10. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium

Author: Rl, Milne, Herranz J, Michailidou K, Joe Dennis, Jp, Tyrer, Mp, Zamora, Ji, Arias-Perez, González-Neira A, Pita G, Alonso MR, Wang Q, Mk, Bolla, Czene K, Eriksson M, Humphreys K, Darabi H, Li J, Anton-Culver H, Sl, Neuhausen, Ziogas A, Ca, Clarke, Jl, Hopper, Gs, Dite, Apicella C, Mc, Southey, Chenevix-Trench G, kConFab Investigators, Australian Ovarian Cancer Study Group, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Il, Andrulis, Ja, Knight, Glendon G, Am, Mulligan, Se, Bojesen, Bg, Nordestgaard, Flyger H, Nevanlinna H, Ta, Muranen, Aittomäki K, Blomqvist C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Je, Olson, Vachon C, Purrington K, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Am, Dunning, Shah M, Guénel P, Truong T, Sanchez M, Mulot C, Brenner H, Ak, Dieffenbach, Arndt V, Stegmaier C, Lindblom A, Margolin S, Hooning M, Hollestelle A, Collée M, Jager A, Cox A, Iw, Brock, Mw, Reed, Devilee P, Ra, Tollenaar, Seynaeve C, Ca, Haiman, Be, Henderson, Schumacher F, Le Marchand L, Simard J, Dumont M, Soucy P, Dörk T, Nv, Bogdanova, Hamann U, Försti A, Rüdiger T, Hu, Ulmer, Pa, Fasching, Häberle L, Ab, Ekici, Mw, Beckmann, Fletcher O, Johnson N, Id, Silva, Peto J, Radice P, Peterlongo P, Peissel B, Mariani P, Gg, Giles, Severi G, Baglietto L, Sawyer E, Tomlinson I, Kerin M, Miller N, Marme F, Burwinkel B, Mannermaa A, Kataja V, Vm, Kosma, Hartikainen J, Lambrechts D, Bt, Yesilyurt, Floris G, Leunen K, Gg, Alnæs, Kristensen V, Al, Børresen-Dale, García-Closas M, Sj, Chanock, Lissowska J, Jd, Figueroa, Mk, Schmidt, Broeks A, Verhoef S, Ej, Rutgers, Brauch H, Brüning T, Yd, Ko, Genica, The Network, Fj, Couch, Ae, Toland, Tnbcc, The, Yannoukakos D, Pd, Pharoah, Hall P, Benítez J, Malats N, and Df, Easton
Subjects: Australian Ovarian Cancer Study Group, Genetics & Heredity, Breast Neoplasms, Epistasis, Genetic, Biological Sciences, TNBCC, Polymorphism, Single Nucleotide, Medical and Health Sciences, Logistic Models, Case-Control Studies, kConFab Investigators, Humans, Genetic Predisposition to Disease, Female, GENICA Network, Genome-Wide Association Study
Abstract: Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
Published: 2014

11. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Author: Sawyer, E, Roylance, R, Petridis, C, Brook, MN, Nowinski, S, Papouli, E, Fletcher, O, Pinder, S, Hanby, A, Kohut, K, Gorman, P, Caneppele, M, Peto, J, Silva, ID, Johnson, N, Swann, R, Dwek, M, Perkins, KA, Gillett, C, Houlston, R, Ross, G, De Ieso, P, Southey, MC, Hopper, JL, Provenzano, E, Apicella, C, Wesseling, J, Cornelissen, S, Keeman, R, Fasching, PA, Jud, SM, Ekici, AB, Beckmann, MW, Kerin, MJ, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Laurent-Puig, P, Kerbrat, P, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Perez, JIA, Menendez, P, Benitez, J, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Lochmann, M, Brauch, H, Fischer, HP, Ko, YD, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Chenevix-Trench, G, Lambrechts, D, Weltens, C, van Limbergen, E, Hatse, S, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Giles, GG, Severi, G, Baglietto, L, McLean, CA, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Kristensen, V, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Tollenaar, RAEM, Seynaeve, Caroline, Kriege, Mieke, Figueroa, J, Chanock, SJ, Sherman, ME, Hooning, Maartje, Hollestelle, Antoinette, van den Ouweland, Ans, van Deurzen, Carolien, Li, JM, Czene, K, Humphreys, K, Cox, A, Cross, SS, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Couch, FJ, Hallberg, E, Gonzalez-Neira, A, Pita, G, Alonso, MR, Tessier, DC, Vincent, D, Bacot, F, Bolla, MK, Wang, Q (Qing), Dennis, J, Michailidou, K, Dunning, AM, Hall, P, Easton, D, Pharoah, P, Schmidt, Marjanka K, Tomlinson, I, Garcia-Closas, M, Medical Oncology, Clinical Genetics, and Pathology
Subjects: body regions, SDG 3 - Good Health and Well-being, skin and connective tissue diseases
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95% CI) for ILC = 1.13 (1.09-1.18), P = 6.0x10(-10); P-het for ILC vs IDC ER+ tumors = 1.8x10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P
Published: 2014

12. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author: Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, JI, Zamora, MP, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q (Qing), Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, YD, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, JM, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, MR, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, RX, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, Maartje, Kriege, Mieke, van den Ouweland, Ans, Koppert, Linetta, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, JR, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK (Marjanka), Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, JY, Park, SK, Noh, DY, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, WT, Shen, CY, Hsiung, CN, Yu, JC, Hou, MF, Guenel, P, Sanchez, M, Mulot, C, Blot, W, Cai, QY, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Bogdanova, N, Dork, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Shu, XO, Lu, W, Gao, YT, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, Mckay, J, Wang, XS, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S (Shahana), Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, Easton, DF, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Surgery
Subjects: SDG 3 - Good Health and Well-being
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Published: 2014

13. Exome sequencing of three cases of familial exceptional longevity

Author: Cash TP, Pita G, Domínguez O, Alonso MR, Moreno LT, Borrás C, Rodríguez-Mañas L, Santiago C, Garatachea N, Lucia A, Avellana JA, Viña J, González-Neira A, and Serrano M
Subjects: apolipoprotein B, centenarians, exome sequencing, longevity, rare variants
Abstract: Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands = 103 years and at least one sibling = 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have = 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5-13) or within individual families (66-156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.
Published: 2014

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

Author: Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, Garcia-Closas, M, Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, and Garcia-Closas, M
Abstract: BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
Published: 2015

15. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Author: Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, French, JD, Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, and French, JD
Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Published: 2015

16. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author: Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Dos Santos Silva, I, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittom Currency Signki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Müller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guénel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Alonso, MR, Gonzlez-Neira, A, Ben-tez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Müller, H, Arndt, V, Stegmaier, C, Justenhoven, C, and Brauch, H
Abstract: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for g1/48% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in g1/470,000 cases and ĝ̂1/468,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 - 10 g35), 12q24 (rs1292011; P = 4.3 - 10 g19) and 21q21 (rs2823093; P = 1.1 - 10 g12). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

17. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Author: Gibson, G, Sawyer, E, Roylance, R, Petridis, C, Brook, MN, Nowinski, S, Papouli, E, Fletcher, O, Pinder, S, Hanby, A, Kohut, K, Gorman, P, Caneppele, M, Peto, J, Silva, IDS, Johnson, N, Swann, R, Dwek, M, Perkins, K-A, Gillett, C, Houlston, R, Ross, G, De Ieso, P, Southey, MC, Hopper, JL, Provenzano, E, Apicella, C, Wesseling, J, Cornelissen, S, Keeman, R, Fasching, PA, Jud, SM, Ekici, AB, Beckmann, MW, Kerin, MJ, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Laurent-Puig, P, Kerbrat, P, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Perez, JIA, Menendez, P, Benitez, J, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Lochmann, M, Brauch, H, Fischer, H-P, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Lambrechts, D, Weltens, C, Van Limbergen, E, Hatse, S, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Giles, GG, Severi, G, Baglietto, L, Mclean, CA, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Kristensen, V, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Tollenaar, RAEM, Seynaeve, CM, Kriege, M, Figueroa, J, Chanock, SJ, Sherman, ME, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, van Deurzen, CHM, Li, J, Czene, K, Humphreys, K, Cox, A, Cross, SS, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Couch, FJ, Hallberg, E, Gonzalez-Neira, A, Pita, G, Alonso, MR, Tessier, DC, Vincent, D, Bacot, F, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Dunning, AM, Hall, P, Easton, D, Pharoah, P, Schmidt, MK, Tomlinson, I, Garcia-Closas, M, Gibson, G, Sawyer, E, Roylance, R, Petridis, C, Brook, MN, Nowinski, S, Papouli, E, Fletcher, O, Pinder, S, Hanby, A, Kohut, K, Gorman, P, Caneppele, M, Peto, J, Silva, IDS, Johnson, N, Swann, R, Dwek, M, Perkins, K-A, Gillett, C, Houlston, R, Ross, G, De Ieso, P, Southey, MC, Hopper, JL, Provenzano, E, Apicella, C, Wesseling, J, Cornelissen, S, Keeman, R, Fasching, PA, Jud, SM, Ekici, AB, Beckmann, MW, Kerin, MJ, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Laurent-Puig, P, Kerbrat, P, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Perez, JIA, Menendez, P, Benitez, J, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Lochmann, M, Brauch, H, Fischer, H-P, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Lambrechts, D, Weltens, C, Van Limbergen, E, Hatse, S, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Giles, GG, Severi, G, Baglietto, L, Mclean, CA, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Kristensen, V, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Tollenaar, RAEM, Seynaeve, CM, Kriege, M, Figueroa, J, Chanock, SJ, Sherman, ME, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, van Deurzen, CHM, Li, J, Czene, K, Humphreys, K, Cox, A, Cross, SS, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Couch, FJ, Hallberg, E, Gonzalez-Neira, A, Pita, G, Alonso, MR, Tessier, DC, Vincent, D, Bacot, F, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Dunning, AM, Hall, P, Easton, D, Pharoah, P, Schmidt, MK, Tomlinson, I, and Garcia-Closas, M
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between E
Published: 2014

18. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author: Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
Abstract: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Published: 2014

19. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Author: Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, Milne, RL, Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, and Milne, RL
Abstract: BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
Published: 2014

20. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author: Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Offit, K
Published: 2013

21. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk

Author: Genuardi, Maurizio, Vijai, J, Dicks, E, Soucy, P, Sinilnikova, Om, Pankratz, V, Wang, X, Eldridge, Rc, Tessier, Dc, Vincent, D, Bacot, F, Hogervorst, Fb, Peock, S, Stoppa Lyonnet, D, Barile, M, Alonso, Mr, Kirchhoff, T, Mcguffog, L, Barrowdale, D, Dunning, Am, Lee, A, Klein, Rj, Gaudet, Mm, Kuchenbaecker, Kb, Dennis, J, Healey, S., Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Genuardi, Maurizio, Vijai, J, Dicks, E, Soucy, P, Sinilnikova, Om, Pankratz, V, Wang, X, Eldridge, Rc, Tessier, Dc, Vincent, D, Bacot, F, Hogervorst, Fb, Peock, S, Stoppa Lyonnet, D, Barile, M, Alonso, Mr, Kirchhoff, T, Mcguffog, L, Barrowdale, D, Dunning, Am, Lee, A, Klein, Rj, Gaudet, Mm, Kuchenbaecker, Kb, Dennis, J, Healey, S., and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)
Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of br
Published: 2013

22. Astroseti.org: Online Collaborative Translations for Science Public Outreach

Author: Alonso, Mr. Sergio, primary and González, Mr. Emilio, additional
Published: 2006
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23. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, Easton, DF, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, and Easton, DF

24. Immunotherapies against HER2-Positive Breast Cancer

Author: Macarena Roman Alonso, Joaquin Arribas, Santiago Duro Sánchez, Institut Català de la Salut, [Duro-Sánchez S, Alonso MR] Preclinical & Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. [Arribas J] Preclinical & Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Mama - Càncer - Prognosi, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Vaccines, Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], CAR-Ts, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], terapéutica::terapia biológica::inmunomodulación::inmunoterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Resistance, Other subheadings::/therapy [Other subheadings], afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::progresión de la enfermedad [ENFERMEDADES], TCBs, Oncology, HER2, Mama - Càncer - Immunoteràpia, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression [DISEASES], Immunotherapy, Otros calificadores::/terapia [Otros calificadores]
Abstract: A wide range of treatments are available for HER2-positive breast cancer, which have greatly improved the prognosis and quality of life of these patients. However, resistance to HER2-targeted or untargeted therapies is common in clinical practice and is associated with metastasis, recurrence, and cancer-related death. To address this clinical need, researchers are exploring immunotherapeutic approaches to completely eradicate tumor cells and prevent tumor relapse and progression. In this review, we focus on how these emerging strategies can overcome current resistance and improve the prognosis of patients who do not respond to standard therapies. Breast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15–20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and untargeted, many patients do not respond to therapy and relapse and eventually metastasize, with a poor prognosis. Immunotherapeutic approaches aim to enhance the antitumor immune response to prevent tumor relapse and metastasis. Several immunotherapies have been approved for solid tumors, but their utility for HER2-positive breast cancer has yet to be confirmed. In this review, we examine the different immunotherapeutic strategies being tested in HER2-positive breast cancer, from long-studied cancer vaccines to immune checkpoint blockade, which targets immune checkpoints in both T cells and tumor cells, as well as the promising adoptive cell therapy in various forms. We discuss how some of these new approaches may contribute to the prevention of tumor progression and be used after standard-of-care therapies for resistant HER2-positive breast tumors, highlighting the benefits and drawbacks of each. We conclude that immunotherapy holds great promise for the treatment of HER2-positive tumors, with the potential to completely eradicate tumor cells and prevent the progression of the disease.
Published: 2023

25. Origanum vulgare : peroxidase-, superoxide dismutase- and immunomodulatory activities on macrophages activated with Helicobacter pylori derivatives.

Author: Ferramola FF, Marrassini C, Alonso MR, Mattar Dominguez MA, Vega AE, and Anesini C
Subjects: Animals, Mice, Immunologic Factors pharmacology, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents chemistry, Peroxidase metabolism, RAW 264.7 Cells, Helicobacter pylori drug effects, Macrophages drug effects, Macrophages metabolism, Nitric Oxide metabolism, Superoxide Dismutase metabolism, Plant Extracts pharmacology, Plant Extracts chemistry, Origanum chemistry, Antioxidants pharmacology
Abstract: Helicobacter pylori , invades the gastric mucosa and is one of the causative agents of stomach cancer and peptic ulcers. Origanum vulgare , is a flavouring herb used worldwide. But little is known about the effects of extracts prepared by maceration in cold PBS. This study was aimed at determining the superoxide dismutase (SOD)- and peroxidase (Px)-like antioxidant activities as well as the immunomodulatory activity (anti-inflammatory/pro-inflammatory) of an aqueous extract of O. vulgare by evaluating the production of nitric oxide (NO) in macrophages stimulated with H. pylori derivatives. The cold extract presented SOD-like and Px-like activities with effective concentration 50 (EC50) values of Px = 489.7 ± 48 µg/ml and SOD= 384.7 ± 30 µg/ml. The extract was also capable of modulating the production of NO in macrophages stimulated by H. pylori derivatives by exerting a pro-inflammatory activity at high concentrations and an anti-inflammatory activity at low concentrations.
Published: 2024
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26. Induction of phytoextraction, phytoprotection and growth promotion activities in Lupinus albus under mercury abiotic stress conditions by Peribacillus frigoritolerans subsp., mercuritolerans subsp. nov.

Author: González-Reguero D, Robas-Mora M, Alonso MR, Fernández-Pastrana VM, Lobo AP, and Gómez PAJ
Subjects: Biodegradation, Environmental, Bacillaceae genetics, Spain, Antioxidants metabolism, Plant Roots, Mercury toxicity, Soil Pollutants toxicity, Soil Microbiology, Lupinus microbiology, Stress, Physiological drug effects
Abstract: Strain SAICEUPBM T was isolated from soils of Almadén (Ciudad Real, Spain), subjected to a high mercury concentration. SAICEUPBM T significantly increased aerial plant weight, aerial plant length and the development of secondary roots under mercury stress; increased twice the absorption of mercury by the plant, while favoring its development in terms of biomass. Similarly, plants inoculated with SAICEUPBM T and grown in soils contaminated with mercury, express a lower activity of antioxidant enzymes; catalase enzymes (CAT), superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR) for defense against ROS (reactive oxygen species). Whole genome analysis showed that ANI (95. 96 %), dDDH (72.9 %), AAI (93.3 %) and TETRA (0.99) values were on the thresholds established for differentiation a subspecies. The fatty acids analysis related the strain with the Peribacillus frigoritolerans species. And the synapomorphic analysis reveals a common ancestor with analysis related the strain with the Peribacillus frigoritolerans species. Results from genomic analysis together with differences in phenotypic features and chemotaxonomic analysis support the proposal of strain SAICEUPBM T as the type strain of a novel subspecies for which the name Peribacillus frigoritolerans subps. mercuritolerans sp. nov is proposed. The absence of virulence genes and transmissible resistance mechanisms reveals its safety for agronomic uses, under mercury stress conditions. The ability of Peribacillus frigoritolerans subsp. mercuritolerans subsp. nov to improve plant development was tested in a Lupinus albus model, demonstrating a great potential for plant phytoprotection against mercury stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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27. In Vitro Antioxidant Activity and Anticonvulsant Properties on Zebrafish PTZ-Induced Seizure Model of a Tilia viridis Aqueous Extract.

Author: Martin EMS, Sosa AM, Martinez CS, Prieto J, Marrassini C, Dobrecky CB, Alonso MR, and Anesini C
Abstract: Objectives: Tilia viridis (Bayer) Simonk. (Malvaceae) is widely distributed in Argentina and employed for its tranquilizing properties. Other species of the genus ( Tilia europaea L., Tilia cordata Mill., Tilia platyphyllos Scop.) have been traditionally used for the treatment of epilepsy. Epilepsy affects approximately 65 million people worldwide and is characterized by an imbalance between excitatory and inhibitory processes in the brain, leading to unpredictable, unprovoked, recurrent seizures. Current pharmacological interventions often present mild to moderately severe side effects. Epilepsy has been associated with oxidative and nitrative stress as well as neuroinflammation. Herbal medicine therapies may offer new treatment options with multi-target antioxidant and anticonvulsant effects for patients whose seizures remain uncontrolled, potentially providing cost-effective solutions for individuals worldwide suffering from uncontrolled epilepsy.The aim of this study was to demonstrate the anticonvulsant activity of a standardized T. viridis aqueous extract (TE)., Methods: Study of the constituents of TE, TE's antioxidant and anticonvulsant activities and toxicity, and analysis of the possible relation between the potential activities and the compounds present in the extract. In order to demonstrate TE's anticonvulsant activity a zebrafish model was used. The study also assessed TE's toxicity and antioxidant activity. To standardize the extract, total polyphenols and flavonoids were quantified and specific flavonoids were identified and quantified using HPLC-MS/MS and HPLC-UV., Results: TE exhibited anticonvulsant activity at low concentrations and demonstrated antioxidant effects by scavenging free radicals, exhibiting superoxide dismutase and peroxidase-like activities, as well as inhibiting lipoperoxidation. These actions can be attributed to the presence of polyphenols, particularly flavonoids., Conclusion: TE holds promise as a complementary herbal medicine in the treatment of epilepsy and may also offer benefits for other neuropathies associated with oxidative stress, such as Parkinson's disease and Alzheimer's disease., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest in this work., (© 2024 Korean Pharmacopuncture Institute.)
Published: 2024
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28. Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.

Author: Davidson AL, Michailidou K, Parsons MT, Fortuno C, Bolla MK, Wang Q, Dennis J, Naven M, Abubakar M, Ahearn TU, Alonso MR, Andrulis IL, Antoniou AC, Auvinen P, Behrens S, Bermisheva MA, Bogdanova NV, Bojesen SE, Brüning T, Byers HJ, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Collée JM, Czene K, Dörk T, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Gronwald J, Guénel P, Hadjisavvas A, Haeberle L, Hall P, Hamann U, Hartman M, Ho PJ, Hooning MJ, Hoppe R, Howell A, Jakubowska A, Khusnutdinova EK, Kristensen VN, Li J, Lim J, Lindblom A, Liu J, Lophatananon A, Mannermaa A, Mavroudis DA, Mensenkamp AR, Milne RL, Muir KR, Newman WG, Obi N, Panayiotidis MI, Park SK, Park-Simon TW, Peterlongo P, Radice P, Rashid MU, Rhenius V, Saloustros E, Sawyer EJ, Schmidt MK, Seibold P, Shah M, Southey MC, Teo SH, Tomlinson I, Torres D, Truong T, van de Beek I, van der Hout AH, Wendt CC, Dunning AM, Pharoah PDP, Devilee P, Easton DF, James PA, and Spurdle AB
Subjects: Humans, Female, BRCA2 Protein genetics, BRCA1 Protein genetics, Fanconi Anemia Complementation Group N Protein genetics, Middle Aged, Mutation, Missense genetics, Adult, Tumor Suppressor Protein p53 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation genetics
Abstract: Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels., Competing Interests: Declaration of interests P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of VUSs in BRCA1 and BRCA2. The funds were paid to the institution., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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29. Inhibition of Glycation End Products Formation and Antioxidant Activities of Ilex paraguariensis : comparative study of fruit and leaves extracts.

Author: Cogoi L, Marrassini C, Martin EMS, Alonso MR, Filip R, and Anesini C
Abstract: Objectives: Ilex paraguariensis (Aquifoleaceae) is cultivated to produce "yerba mate". Due to its nutritional, energizing, hypoglycemic and antioxidant effects, it is used in the elaboration of food, pharmaceuticals, and cosmetics. The oxidative stress related to protein glycation and production of advanced glycation end products (AGEs) leads to the development of several diseases. The objective of this work was to compare the antioxidant and anti-AGEs activity of a decoction of fruits (F) and leaves (L)., Methods: The antioxidant activity was assayed by the DPPH assay and the inhibition of egg yolk lipid peroxidation (ILP), and anti-AGEs activity, through the inhibition of the formation of fructosamine (IF), β-amyloid (Iβ), protein carbonylation (IC) and AGEs (IA). Polyphenols were quantified by HPLC., Results: Maximum response ± SEM For F 0.01 µg/mL IF = 42 ± 4%, IC = 17 ± 2% and for 10 µg/mL IA = 38 ± 4%, Iβ = 67 ± 7%. For L 0.1 µg/mL IF = 35 ± 2%, IC = 19 ± 2% and for 100 µg/mL IA = 26 ± 3%, Iβ = 63.04 ± 2%. The DPPH IC 50 = 134.8 ± 14 µg/mL for F and 34.67 ± 3 µg/mL for L. The ILP IC 50 = 512.86 ± 50 µg/mL for F and 154.8 ± 15 µg/mL for L. By HPLC L presented the highest amounts of flavonoids and caffeoylquinic acids. F and L showed strong anti-AGEs activity, affecting the early stages of glycation at low concentrations and the late stages of glycation at high concentrations. The highest activity for both F and L was seen in the IF and Iβ. F presented the highest anti-AGEs potency. L presented the highest antioxidant potency, which was related to the highest content of polyphenols., Conclusion: The fruits of I. paraguariensis could be a source of antioxidant and anti-AGEs compounds to be used with medicinal purposes or as functional food., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest regarding the publication of this paper., (© 2023 Korean Pharmacopuncture Institute.)
Published: 2023
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30. Author Correction: Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Author: Wilcox N, Dumont M, González-Neira A, Carvalho S, Joly Beauparlant C, Crotti M, Luccarini C, Soucy P, Dubois S, Nuñez-Torres R, Pita G, Gardner EJ, Dennis J, Alonso MR, Álvarez N, Baynes C, Collin-Deschesnes AC, Desjardins S, Becher H, Behrens S, Bolla MK, Castelao JE, Chang-Claude J, Cornelissen S, Dörk T, Engel C, Gago-Dominguez M, Guénel P, Hadjisavvas A, Hahnen E, Hartman M, Herráez B, Jung A, Keeman R, Kiechle M, Li J, Loizidou MA, Lush M, Michailidou K, Panayiotidis MI, Sim X, Teo SH, Tyrer JP, van der Kolk LE, Wahlström C, Wang Q, Perry JRB, Benitez J, Schmidt MK, Schmutzler RK, Pharoah PDP, Droit A, Dunning AM, Kvist A, Devilee P, Easton DF, and Simard J
Published: 2023
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31. Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Author: Wilcox N, Dumont M, González-Neira A, Carvalho S, Joly Beauparlant C, Crotti M, Luccarini C, Soucy P, Dubois S, Nuñez-Torres R, Pita G, Gardner EJ, Dennis J, Alonso MR, Álvarez N, Baynes C, Collin-Deschesnes AC, Desjardins S, Becher H, Behrens S, Bolla MK, Castelao JE, Chang-Claude J, Cornelissen S, Dörk T, Engel C, Gago-Dominguez M, Guénel P, Hadjisavvas A, Hahnen E, Hartman M, Herráez B, Jung A, Keeman R, Kiechle M, Li J, Loizidou MA, Lush M, Michailidou K, Panayiotidis MI, Sim X, Teo SH, Tyrer JP, van der Kolk LE, Wahlström C, Wang Q, Perry JRB, Benitez J, Schmidt MK, Schmutzler RK, Pharoah PDP, Droit A, Dunning AM, Kvist A, Devilee P, Easton DF, and Simard J
Subjects: Female, Humans, Exome Sequencing, Mutation, Missense genetics, Exome genetics, Neoplasms
Abstract: Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10 -6 ): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10 -4 . Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small., (© 2023. The Author(s).)
Published: 2023
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32. Antiprotozoal compounds from Mikania periplocifolia (Asteraceae).

Author: Laurella LC, Elso OG, Rodriguez RN, Viecenz JM, Alonso MR, Bontempi EJ, Malchiodi E, Catalán CAN, Cazorla SI, and Sülsen VP
Subjects: Animals, Humans, Methylene Chloride therapeutic use, Plant Extracts chemistry, Molecular Structure, Flavonoids pharmacology, Lactones, Mammals, Asteraceae chemistry, Mikania chemistry, Antiprotozoal Agents pharmacology, Trypanosoma cruzi, Leishmaniasis drug therapy, Sesquiterpenes
Abstract: Chagas disease, African trypanosomiasis and Leishmaniasis are neglected parasitic diseases which affect millions of people worldwide. In a previous work, we report the antiprotozoal activity of the dichloromethane extract of Mikania periplocifolia Hook. & Arn. (Asteraceae). The aim of this work was to isolate and identify the bioactive compounds present in the extract. The fractionation of the dichloromethane extract has led to the isolation of the sesquiterpene lactone miscandenin and the flavonoid onopordin, together with the sesquiterpene lactones mikanolide, dihydromikanolide and deoxymikanolide, which have previously shown antiprotozoal activity. Miscandenin and onopordin were assayed in vitro against Trypanosoma cruzi, T. brucei and Leishmania braziliensis. Miscandenin was active against T. cruzi trypomastigotes and amastigotes with IC 50 values of 9.1 and 7.7 μg/ml, respectively. This sesquiterpene lactone and the flavonoid onopordin showed activity against T. brucei trypomastigotes (IC 50 = 0.16 and 0.37 μg/ml) and L. braziliensis promastigotes (IC 50 = 0.6 and 1.2 μg/ml), respectively. The CC 50 values on mammalian cells were 37.9 and 53.4 μg/ml for miscandenin and onopordin, respectively. Besides, the pharmacokinetic and physicochemical properties of miscandenin were assessed in silico, showing a good drug-likeness profile. Our results highlight this compound as a promising candidate for further preclinical studies in the search of new drugs for the treatment of trypanosomiasis and leishmaniasis., Competing Interests: Declaration of Competing Interest The authors do not have any conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)
Published: 2023
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33. A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.

Author: Nunez-Torres R, Pita G, Peña-Chilet M, López-López D, Zamora J, Roldán G, Herráez B, Álvarez N, Alonso MR, Dopazo J, and Gonzalez-Neira A
Abstract: The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.
Published: 2023
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34. Immunotherapies against HER2-Positive Breast Cancer.

Author: Duro-Sánchez S, Alonso MR, and Arribas J
Abstract: Breast cancer is the leading cause of cancer-related deaths among women worldwide. HER2-positive breast cancer, which represents 15-20% of all cases, is characterized by the overexpression of the HER2 receptor. Despite the variety of treatments available for HER2-positive breast cancer, both targeted and untargeted, many patients do not respond to therapy and relapse and eventually metastasize, with a poor prognosis. Immunotherapeutic approaches aim to enhance the antitumor immune response to prevent tumor relapse and metastasis. Several immunotherapies have been approved for solid tumors, but their utility for HER2-positive breast cancer has yet to be confirmed. In this review, we examine the different immunotherapeutic strategies being tested in HER2-positive breast cancer, from long-studied cancer vaccines to immune checkpoint blockade, which targets immune checkpoints in both T cells and tumor cells, as well as the promising adoptive cell therapy in various forms. We discuss how some of these new approaches may contribute to the prevention of tumor progression and be used after standard-of-care therapies for resistant HER2-positive breast tumors, highlighting the benefits and drawbacks of each. We conclude that immunotherapy holds great promise for the treatment of HER2-positive tumors, with the potential to completely eradicate tumor cells and prevent the progression of the disease.
Published: 2023
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35. Anti-hyperglycaemic effect and nutritional properties of an aqueous extract of Larrea divaricata Cav. (jarilla) in streptozotocin-induced diabetes in mice.

Author: Peralta I, Marrassini C, Saint Martin M, Plantamura YS, Cogoi L, Pellegrino N, Alonso MR, and Anesini C
Subjects: Animals, Antioxidants pharmacology, Antioxidants therapeutic use, Glucose, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Masoprocol pharmacology, Mice, Plant Extracts pharmacology, Plant Extracts therapeutic use, Streptozocin, Triglycerides, Water, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Experimental drug therapy, Larrea
Abstract: Ethnopharmacological Relevance: Larrea divaricata Cav. (Zygophyllaceae) (jarilla) is a native plant of South America widely distributed across Argentina and used in popular medicine to treat diabetes and hypercholesterolemia by the Diaguita-Calchaquí, Amaichas, and Quilmes indigenous communities and by non-indigenous population (criollos) of Calamuchita, in the province of Córdoba, Argentina. L. divaricata has also proved to have anti-inflammatory properties. However, the antidiabetic effects and the nutritional properties of the aqueous extract (AE) of this plant remain to be scientifically determined., Aim of the Study: The aim of the present work was to evaluate the capacity of an aqueous extract of L. divaricata (AE) and its main compound nordihydroguaiaretic acid (NDGA) to modulate the glucose, cholesterol, triglycerides and oxidative stress levels in STZ-induced diabetes in mice. The general objective of the present work was to search for extracts that can be used as adjuvant therapy in for diabetes. The suitability of the extract to be used as a dietary supplement was also assessed by determining the proximate amount of fibre, lipids, proteins, and minerals., Materials and Methods: Diabetes was induced in mice by administration of streptozotocin (STZ). AE and NDGA were administered by the oral route. The animals' glycaemia was periodically monitored in blood samples obtained from the tail vein. The glucose dehydrogenase method was used. The effect of the AE on cholesterol, triglycerides, oxidative stress, lipid peroxidation and reduced glutathione (GSH) levels were determined in plasma samples by spectrophotometric assays., Results: In STZ-treated mice, AE significantly decreased glucose (33%, ****p < 0.0001) and cholesterol levels (32%, **p < 0.01). AE and NDGA decreased lipid peroxidation (30% and 38%, respectively, ****p < 0.0001), and increased GSH levels (20%, **p < 0.01). The effects of AE on glucose and lipid levels could not be ascribed to NDGA; however, this compound was involved in the extract antioxidant effects. The overall effects of AE were probably related to its antioxidant activity and to the anti-hyperglycaemic effect mainly mediated by flavonoids, fibre (carbohydrates) and mineral elements such as potassium, calcium, magnesium, and zinc. The AE protein content also confers the extract nutritional properties., Conclusions: These results support the hypothesis that AE could be used as a therapeutic adjuvant or as a nutritional supplement to control glucose levels and lipid metabolism in metabolic syndrome-associated diseases. Moreover, these results scientifically reinforce the popular use of the plant., (Copyright © 2022 Elsevier B.V. All rights reserved.)
Published: 2022
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36. Antiproliferative activity of aqueous and polyphenol-rich extracts of Larrea divaricata Cav. on a melanoma cell line.

Author: Martino R, Barreiro Arcos ML, Peralta I, Marrassini C, Saint Martin EM, Cogoi L, Cremaschi G, Alonso MR, and Anesini C
Subjects: Cell Line, Cell Line, Tumor, Humans, Plant Extracts chemistry, Plant Extracts pharmacology, Polyphenols pharmacology, Water, Larrea chemistry, Melanoma drug therapy
Abstract: Most of the deaths from skin cancer are caused by melanoma, a malignancy in which STAT3 plays a crucial role. The inhibition of STAT3 is considered a potential target to induce cell death, tumor regression and metastasis inhibition. The objective of this work was to evaluate the activity of the aqueous extract of Larrea divaricata (Aq), a fraction rich in polyphenols (EA),and the isolated compound quercetin-3-methyl ether (Q3ME) on B16F10 melanoma cells. The effects of Aq, EA and Q3ME were assessed on B16F10 cells by determining the proliferation, viability, apoptosis induction and the expression and phosphorylation of STAT3. The phytochemical composition of the extracts was determined by High Performance Liquid Chromatography. Aq, EA and Q3ME presented antiproliferative activity on B6F10 cells through p-STAT3 inhibition and early and late apoptosis induction (EC 50 EA= ≤0.1 µg/ml; Aq= 316 ± 30 µg/ml; Q3ME= <0.1 µg/ml). L. divaricata could be considered for the development of adjuvant phytotherapies in melanoma treatment.
Published: 2022
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37. Correction: Larrea divaricata: anti-inflammatory and antioxidant effects on macrophages and low density lipoproteins.

Author: Peralta I, Marrassini C, Saint Martin M, Cogoi L, Alonso MR, Gugliucci A, and Anesini C
Published: 2022
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38. Endoscopic ultrasound-guided gallbladder drainage as rescue treatment after clinical failure of endoscopic choledochoduodenostomy.

Author: de la Serna Gamboa A, López Durán S, González Alonso MR, Vázquez-Sequeiros E, and Albillos Martínez A
Subjects: Drainage, Endosonography, Humans, Stents, Treatment Outcome, Ultrasonography, Interventional, Choledochostomy, Gallbladder diagnostic imaging, Gallbladder surgery
Published: 2022
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39. Larrea divaricata: anti-inflammatory and antioxidant effects of on macrophages and low density lipoproteins.

Author: Peralta I, Marrassini C, Saint Martin M, Cogoi L, Alonso MR, Gugliucci A, and Anesini C
Subjects: Humans, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antioxidants pharmacology, Larrea chemistry, Lipoproteins, LDL metabolism, Macrophages drug effects, Plant Extracts pharmacology
Abstract: Background: The oxidized low density lipoprotein (ox-LDL) contributes to inflammation and oxidative stress through the activation of macrophages under hyperglycemia contributing to the development of diabetes mellitus and to atherosclerosis. Plants are a source of effective and innocuous antioxidants. Larrea divaricata Cav. (Zygophyllaceae) is used in Argentina folk medicine for its anti-inflammatory properties., Methods: The aim of this work was to study the antioxidant and anti-inflammatory effects of the aqueous extract (AE) of L. divaricata on macrophages under glucose stimulation and on human LDL and HDL particles under free radical generators., Results: AE reduced the lipid peroxidation (17%), nitric oxide (NO) (47-50%), tumor necrosis factor-α (TNF-α) (32%) and free radicals (50%) induced by glucose on macrophages. Also prevented HDL nitration (28%), thus preserving its function and structure and inhibited LDL oxidation. The effect on the nitrosative stress was mainly driven by nordihydroguaiaretic acid (NDGA)., Conclusions: These results suggest a potential usefulness of AE as an adjuvant phytotherapy in patients with diabetes mellitus and atherosclerosis., (© 2022. The Author(s).)
Published: 2022
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40. PTSD symptomatology is selectively associated with impaired sustained attention ability and dorsal attention network synchronization.

Author: Evans TC, Alonso MR, Jagger-Rickels A, Rothlein D, Zuberer A, Bernstein J, Fortier CB, Fonda JR, Villalon A, Jorge R, Milberg W, McGlinchey R, DeGutis J, and Esterman M
Subjects: Humans, Brain, Magnetic Resonance Imaging, Neuropsychological Tests, Stress Disorders, Post-Traumatic, Veterans
Abstract: Posttraumatic Stress Disorder (PTSD) symptomatology is associated with dysregulated sustained attention, which produces functional impairments. Performance on sustained attention paradigms such as continuous performance tasks are influenced by both the ability to sustain attention and response strategy. However, previous studies have not dissociated PTSD-related associations with sustained attention ability and strategy, which limits characterization of neural circuitry underlying PTSD-related attentional impairments. Therefore, we characterized and replicated PTSD-related associations with sustained attention ability and response strategy in trauma-exposed Veterans, which guided characterization of PTSD-related differences in neural circuit function. In Study 1, PTSD symptoms were selectively associated with reduced sustained attention ability, but not more impulsive response strategies. In Study 2, we utilized task and resting-state fMRI to characterize neural circuitry underlying PTSD-related differences in sustained attention ability. Both PTSD symptomatology and sustained attention ability exhibited converging associations with reduced dorsal attention network (DAN) synchronization to endogeneous attentional fluctuations. Post-hoc time course analyses demonstrated that PTSD symptoms were most accurately characterized by delayed, rather than globally reduced, DAN synchronization to endogenous attentional fluctuations. Together, these findings suggest that PTSD symptomatology may selectively impair sustained attention ability by disrupting proactive engagement of attentional control circuitry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
Published: 2022
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41. POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients.

Author: Velasco-Ruiz A, Nuñez-Torres R, Pita G, Wildiers H, Lambrechts D, Hatse S, Delombaerde D, Van Brussel T, Alonso MR, Alvarez N, Herraez B, Vulsteke C, Zamora P, Lopez-Fernandez T, and Gonzalez-Neira A
Abstract: Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10 -5 ). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT , a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.
Published: 2021
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42. Environmental assessment of Obstacle Limitation Surfaces (OLS) in airports using geographic information technologies.

Author: Contreras-Alonso MR, Ezquerra-Canalejo A, Pérez-Martín E, Herrero-Tejedor TR, and López-Cuervo Medina S
Subjects: Information Technology, Airports, Crops, Agricultural growth & development, Environmental Monitoring methods, Geographic Information Systems, Risk Assessment methods
Abstract: A series of 3D obstacle limitation surfaces (OLS) define the limits to which objects may project in the airspace in order to configure the airspace around aerodromes that must be kept free from obstacles. The aim is to ensure that aircraft can safely carry out their scheduled operations, and to prevent the aerodromes from becoming unusable due to the proliferation of obstacles in the surrounding area. One such possible obstacle is the vegetation growing in the zone. This work consists of a study of the variation in the vegetation in the El Prat airport (Barcelona-El Prat Josep Tarradellas) and the surrounding area in the years 2011-2018, and of the way in which it has influenced the configuration of the OLS. Until 2010, obstacle studies were carried out every four years but the growth of plant obstacles during this period was not controlled. Although the rate of tree growth depends on several factors such as age, species, site quality and forestry treatment, the parameter analysed in this research is height, as this is what will interfere in the OLS. This study therefore focuses on measuring the height and geolocation of the obstacle in order to determine its influence on the OLS, and on determining the subsequent actions, if any, that need to be taken in regard to this vegetation element to avoid it becoming a risk to operational safety. As a result, the growth and vulnerability of 84 vegetation obstacles from 794 terrain elements have been detected. The result of this study is the design, using geographic information systems, of a tool to assist airport managers in the automated control and monitoring of the vegetation in the obstacle limitation surfaces to avoid compromising the safety of airport operations and mitigating environmental impacts., Competing Interests: The authors have declared that no competing interests exist.
Published: 2020
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43. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author: Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K, Alonso MR, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Aronson KJ, Arun BK, Auber B, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Beeghly-Fadiel A, Benitez J, Bermisheva M, Białkowska K, Blanco AM, Blomqvist C, Blot W, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Bosse K, Brauch H, Brenner H, Briceno I, Brock IW, Brooks-Wilson A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldés T, Caligo MA, Camp NJ, Campbell I, Canzian F, Carroll JS, Carter BD, Castelao JE, Chiquette J, Christiansen H, Chung WK, Claes KBM, Clarke CL, Collée JM, Cornelissen S, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Domchek SM, Dörk T, Dos-Santos-Silva I, Droit A, Dubois S, Dumont M, Duran M, Durcan L, Dwek M, Eccles DM, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Floris G, Flyger H, Foretova L, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gago-Dominguez M, Gambino G, Ganz PA, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Tibiletti MG, Greene MH, Grip M, Gronwald J, Grundy A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hartikainen JM, Hartman M, He W, Healey CS, Heemskerk-Gerritsen BAM, Heyworth J, Hillemanns P, Hogervorst FBL, Hollestelle A, Hooning MJ, Hopper JL, Howell A, Huang G, Hulick PJ, Imyanitov EN, Isaacs C, Iwasaki M, Jager A, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kang D, Kapoor PM, Karlan BY, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Kirk J, Kitahara CM, Ko YD, Konstantopoulou I, Kosma VM, Koutros S, Kubelka-Sabit K, Kwong A, Kyriacou K, Laitman Y, Lambrechts D, Lee E, Leslie G, Lester J, Lesueur F, Lindblom A, Lo WY, Long J, Lophatananon A, Loud JT, Lubiński J, MacInnis RJ, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matsuo K, Maurer T, Mavroudis D, Mayes R, McGuffog L, McLean C, Mebirouk N, Meindl A, Miller A, Miller N, Montagna M, Moreno F, Muir K, Mulligan AM, Muñoz-Garzon VM, Muranen TA, Narod SA, Nassir R, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nikitina-Zake L, Norman A, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Osorio A, Pankratz VS, Papp J, Park SK, Park-Simon TW, Parsons MT, Paul J, Pedersen IS, Peissel B, Peshkin B, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Prokofyeva D, Pujana MA, Pylkäs K, Radice P, Ramus SJ, Rantala J, Rau-Murthy R, Rennert G, Risch HA, Robson M, Romero A, Rossing M, Saloustros E, Sánchez-Herrero E, Sandler DP, Santamariña M, Saunders C, Sawyer EJ, Scheuner MT, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Scott C, Scott RJ, Senter L, Seynaeve CM, Shah M, Sharma P, Shen CY, Shu XO, Singer CF, Slavin TP, Smichkoska S, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Stoppa-Lyonnet D, Sutter C, Swerdlow AJ, Tamimi RM, Tan YY, Tapper WJ, Taylor JA, Teixeira MR, Tengström M, Teo SH, Terry MB, Teulé A, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Torres-Mejía G, Troester MA, Truong T, Tung N, Tzardi M, Ulmer HU, Vachon CM, van Asperen CJ, van der Kolk LE, van Rensburg EJ, Vega A, Viel A, Vijai J, Vogel MJ, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wildiers H, Winqvist R, Wolk A, Wu AH, Yannoukakos D, Zhang Y, Zheng W, Hunter D, Pharoah PDP, Chang-Claude J, García-Closas M, Schmidt MK, Milne RL, Kristensen VN, French JD, Edwards SL, Antoniou AC, Chenevix-Trench G, Simard J, Easton DF, Kraft P, and Dunning AM
Subjects: Bayes Theorem, Female, Humans, Linkage Disequilibrium, Regulatory Sequences, Nucleic Acid, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Chromosome Mapping methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Published: 2020
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44. Larrea divaricata Cav. aqueous extract and nordihydroguariaretic acid modulate oxidative stress in submandibular glands of diabetic rats: a buccal protective in diabetes.

Author: Peralta I, Marrassini C, Arcos MLB, Cremaschi G, Alonso MR, and Anesini C
Subjects: Animals, Antioxidants pharmacology, Female, Malondialdehyde analysis, Oxidoreductases analysis, Rats, Rats, Wistar, Submandibular Gland chemistry, Submandibular Gland enzymology, Diabetes Mellitus, Experimental metabolism, Larrea chemistry, Masoprocol pharmacology, Oxidative Stress drug effects, Plant Extracts pharmacology, Submandibular Gland drug effects
Abstract: Background: Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and pathogenesis of several oral diseases are attributed to this process. The antioxidant enzymes secreted in the saliva by submandibular glands maintain oral health through the scavenging of ROS. The objective of this work was to study the capacity of an aqueous extract of L. divaricata (AE), and its majority compound, nordihydroguariaretic acid (NDGA), to modulate the pro-oxidant/antioxidant status in submandibular glands in a model of oxidative stress induced by streptozotocin (STZ) in rats., Methods: To induce oxidative stress with STZ, a group of animals was treated i.p. with 1 X PBS (control group) and other group was injected i.p. once with STZ (60 mg/kg). Ten days after the treatment, blood samples were taken from the tail vain to determine the glucose levels. Animals with glucose values ≥300 mg/ml were selected. The submandibular glands of control and STZ treated animals were incubated with either the AE (500 μg/ml) or with NDGA (1.5 μg/ml), and the content of malondialdehyde (MDA), protein carbonyl groups, ROS and RNS, and the activity and expression of peroxidase (Px), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were assayed., Results: AE decreased the levels of MDA ( ## P < 0.01) and protein carbonyl groups ( # P < 0.05), and modulated the levels of ROS such as hydrogen peroxide (H 2 O 2 )( ## P < 0.01), superoxide anion (O 2 .- ) ( # P < 0.05) and nitric oxide (NO) ( # P < 0.05) in relation to the modulation of Px and iNOS expression. NDGA was found to be involved in these effects., Conclusions: The antioxidant activity of the AE in the submandibular glands would allow the maintenance of the antioxidant pool to prevent oral oxidative diseases.
Published: 2019
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45. Gain-of-function mutations in DNMT3A in patients with paraganglioma.

Author: Remacha L, Currás-Freixes M, Torres-Ruiz R, Schiavi F, Torres-Pérez R, Calsina B, Letón R, Comino-Méndez I, Roldán-Romero JM, Montero-Conde C, Santos M, Pérez LI, Pita G, Alonso MR, Honrado E, Pedrinaci S, Crespo-Facorro B, Percesepe A, Falcioni M, Rodríguez-Perales S, Korpershoek E, Ramón-Maiques S, Opocher G, Rodríguez-Antona C, Robledo M, and Cascón A
Subjects: Adrenal Gland Neoplasms pathology, Adult, CRISPR-Cas Systems genetics, DNA Methylation, DNA Methyltransferase 3A, Female, Gain of Function Mutation, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation genetics, Humans, Male, Paraganglioma pathology, Pheochromocytoma pathology, Exome Sequencing, Adrenal Gland Neoplasms genetics, DNA (Cytosine-5-)-Methyltransferases genetics, Paraganglioma genetics, Pheochromocytoma genetics
Abstract: Purpose: The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors., Methods: Whole-exome sequencing was applied to the germlines of a parent-proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed., Results: We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma., Conclusion: Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.
Published: 2018
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46. Window of Implantation is Significantly Displaced in Patients with Adenomyosis with Previous Implantation Failure as Determined by Endometrial Receptivity Assay.

Author: Mahajan N, Kaur S, and Alonso MR
Abstract: Background: Adenomyosis is associated with implantation failure and poor reproductive performance in IVF/ICSI cycles., Aims: To compare if window of implantation (WOI) is displaced in patients having adenomyosis compared to controls using endometrial receptivity array (ERA) test., Settings and Design: Retrospective Case control study. 374 patients with previous one or more IVF failures who underwent ERA test between 2013-2016 at our centre were enrolled. Patients were divided into two groups; Group A-36 patients with adenomyosis (study group) and Group B- 338 patients without adenomyosis (controls)., Statistical Analysis: Normality assumptions for continuous variables were tested using Kolmogorov Smirnov test. Mean values of two groups were compared using Student's t-independent test. Frequency data by categories were compared using Chi-square/Fisher's exact test. Risk ratio and 95% confidence limits were calculated. P < 0.05 was considered for statistical significance., Results: WOI was displaced (Non Receptive ERA) significantly in adenomyosis 47.2% (17/36) compared to controls 21.6% (73/338) ( P < 0.001, CI-8.7%-42.5%) making risk ratio of displaced WOI in adenomyosis versus controls to be 2:1. The incidence of RIF was 66.6% in adenomyosis compared to 34.9% in controls ( P < 0.001, CI- 15.5%-47.9%). Pregnancy rate after personalized embryo transfer in adenomyosis group was 62.5%, signifying displaced WOI as a cause of implantation failure in adenomyosis patients with previous implantation failure., Conclusions: Our study suggests it is prudent to evaluate Endometrial receptivity before embryo transfer in patients with adenomyosis to avoid wastage of good embryos., Competing Interests: There are no conflicts of interest.
Published: 2018
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47. Development of pH-responsive biopolymer-silica composites loaded with Larrea divaricata Cav. extract with antioxidant activity.

Author: Alvarez Echazú MI, Olivetti CE, Peralta I, Alonso MR, Anesini C, Perez CJ, Alvarez GS, and Desimone MF
Subjects: 3T3 Cells, Animals, Antioxidants chemistry, Biopolymers chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Fibroblasts drug effects, Hydrogen-Ion Concentration, Mice, Nanoparticles chemistry, Particle Size, Plant Extracts chemistry, Silicon Dioxide chemistry, Surface Properties, Antioxidants pharmacology, Biopolymers pharmacology, Biphenyl Compounds antagonists & inhibitors, Larrea chemistry, Picrates antagonists & inhibitors, Plant Extracts pharmacology, Silicon Dioxide pharmacology
Abstract: A detailed study of biomaterials is mandatory to comprehend their feasible biomedical applications in terms of drug delivery and tissue regeneration. Particularly, mucoadhesive biopolymers such as chitosan (chi) and carboxymethylcellulose (CMC) have become interesting biomaterials regards to their biocompatibility and non-toxicity for oral mucosal drug delivery. In this work, pH-responsive biopolymer-silica composites (Chi-SiO 2 , Chi-CMC-SiO 2 ) were developed. These two types of composites presented a different swelling behavior due to the environmental pH. Moreover, the nanocomposites were loaded with aqueous Larrea divaricata Cav. extract (Ld), a South American plant which presents antioxidant properties suitable for the treatment of gingivoperiodontal diseases. Chi-CMC-SiO 2 composites showed the highest incorporation and reached the 100% of extract release in almost 4 days while they preserved their antioxidant properties. In this study, thermal and swelling behavior were pointed out to show the distinct water-composite interaction and therefore to evaluate their mucoadhesivity. Furthermore, a cytotoxicity test with 3T3 fibroblasts was assessed, showing that in both composites the addition of Larrea divaricata Cav. extract increased fibroblast proliferation. Lastly, preliminary in vitro studies were performed with simulated body fluids. Indeed, SEM-EDS analysis indicated that only chi-SiO 2 composite may provide an environment for possible biomineralization while the addition of CMC to the composites discouraged calcium accumulation. In conclusion, the development of bioactive composites could promote the regeneration of periodontal tissue damaged throughout periodontal disease and the presence of silica nanoparticles could provide an environment for biomineralization., (Copyright © 2018 Elsevier B.V. All rights reserved.)
Published: 2018
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48. Food preservation by Larrea divaricata extract: participation of polyphenols.

Author: Peralta I, Marrassini C, Filip R, Alonso MR, and Anesini C
Abstract: The aim of this study was to evaluate the antioxidant and protease inhibitor capacities on eggs and milk protein of a nor-dihydroguaiaretic (NDGA)-standardized aqueous extract of Larrea divaricata (AE) and to analyze the participation of polyphenols as NDGA in these actions. NDGA was determined by high-performance liquid chromatography; flavonoids and polyphenols were quantified by spectrophotometric methods as well as inhibition of lipid peroxidation, proteinase inhibitor capacity, advanced glycation end products (AGES) formation, and inhibition of albumin denaturation. The extract protected food for oxidative damage by preventing malondialdehyde formation in egg yolk and by preventing AGE formation in completely cooked eggs, also impeded albumin denaturation, and casein hydrolysis induced by trypsin and heat. Polyphenols, especially flavonoids and NDGA, were involved in these actions.
Published: 2018
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49. Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients.

Author: Ruiz-Pinto S, Pita G, Martín M, Alonso-Gordoa T, Barnes DR, Alonso MR, Herraez B, García-Miguel P, Alonso J, Pérez-Martínez A, Cartón AJ, Gutiérrez-Larraya F, García-Sáenz JA, Benítez J, Easton DF, Patiño-García A, and González-Neira A
Subjects: Adult, Aged, Breast Neoplasms complications, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cancer Survivors, Cardiotoxicity physiopathology, Exome genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Heart Failure chemically induced, Heart Failure genetics, Heart Failure pathology, Humans, Middle Aged, Mitochondria drug effects, Mitochondria pathology, Anthracyclines adverse effects, Breast Neoplasms genetics, Cardiotoxicity genetics, Electron-Transferring Flavoproteins genetics
Abstract: Purpose: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility., Methods: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O)., Results: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10 -4 ) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10 -3 ). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10 -4 , 95% CI 2.83-28.6)., Conclusions: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.
Published: 2018
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50. Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

Author: Ruiz-Pinto S, Pita G, Patiño-García A, Alonso J, Pérez-Martínez A, Cartón AJ, Gutiérrez-Larraya F, Alonso MR, Barnes DR, Dennis J, Michailidou K, Gómez-Santos C, Thompson DJ, Easton DF, Benítez J, and González-Neira A
Subjects: Adolescent, Child, Child, Preschool, Female, Humans, Infant, Leukemia physiopathology, Male, Osteosarcoma complications, Sarcoma, Ewing complications, Anthracyclines adverse effects, Antineoplastic Agents adverse effects, Exome, Genetic Predisposition to Disease, Heart drug effects, Leukemia drug therapy, Osteosarcoma drug therapy, Receptors, G-Protein-Coupled genetics, Sarcoma, Ewing drug therapy
Abstract: Objectives: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients., Patients and Methods: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC., Results: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses., Conclusion: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.
Published: 2017
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