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Dörk, Thilo ; Peterlongo, Peter ; Mannermaa, Arto ; Bolla, Manjeet K. ; Wang, Qin ; Dennis, Joe ; Ahearn, Thomas ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arndt, Volker ; Aronson, Kristan J. ; Augustinsson, Annelie ; Beane Freeman, Laura E. ; Beckmann, Matthias W. ; Beeghly-Fadiel, Alicia ; Behrens, Sabine ; Bermisheva, Marina ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Brauch, Hiltrud ; Brenner, Hermann ; Burwinkel, Barbara ; Canzian, Federico ; Chan, Tsun L. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Choi, Ji-Yeob ; Christiansen, Hans ; Clarke, Christine L. ; Couch, Fergus J. ; Czene, Kamila ; Daly, Mary B. ; dos-Santos-Silva, Isabel ; Dwek, Miriam ; Eccles, Diana M. ; Ekici, Arif B. ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A. ; Figueroa, Jonine ; Flyger, Henrik ; Fritschi, Lin ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Gao, Chi ; Gapstur, Susan M. ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; Giles, Graham G. ; Goldberg, Mark S. ; Goldgar, David E. ; Guenél, Pascal ; Haeberle, Lothar ; Haimann, Christopher A. ; Håkansson, Niclas ; Hall, Per ; Hamann, Ute ; Hartman, Mikael ; Hauke, Jan ; Hein, Alexander ; Hillemanns, Peter ; Hogervorst, Frans B. L. ; Hooning, Maartje J. ; Hopper, John L. ; Howell, Tony ; Huo, Dezheng ; Ito, Hidemi ; Iwasaki, Motoki ; Jakubowska, Anna ; Janni, Wolfgang ; John, Esther M. ; Jung, Audrey ; Kaaks, Rudolf ; Kang, Daehee ; Kapoor, Pooja Middha ; Khusnutdinova, Elza ; Kim, Sung-Won ; Kitahara, Cari M. ; Koutros, Stella ; Kraft, Peter ; Kristensen, Vessela N. ; Kwong, Ava ; Lambrechts, Diether ; Le Marchand, Loic ; Li, Jingmei ; Lindström, Sara ; Linet, Martha ; Lo, Wing-Yee ; Long, Jirong ; Lophatananon, Artitaya ; Lubiński, Jan ; Manoochehri, Mehdi ; Manoukian, Siranoush ; Margolin, Sara ; Martinez, Elena ; Matsuo, Keitaro ; Mavroudis, Dimitris ; Meindl, Alfons ; Menon, Usha ; Milne, Roger L. ; Mohd Taib, Nur Aishah ; Muir, Kenneth ; Mulligan, Anna Marie ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Neven, Patrick ; Newman, William G. ; Offit, Kenneth ; Olopade, Olufunmilayo I. ; Olshan, Andrew F. ; Olson, Janet E. ; Olsson, Håkan ; Park, Sue K. ; Park-Simon, Tjoung-Won ; Peto, Julian ; Plaseska-Karanfilska, Dijana ; Pohl-Rescigno, Esther ; Presneau, Nadege ; Rack, Brigitte ; Radice, Paolo ; Rashid, Muhammad U. ; Rennert, Gad ; Rennert, Hedy S. ; Romero, Atocha ; Ruebner, Matthias ; Saloustros, Emmanouil ; Schmidt, Marjanka K. ; Schmutzler, Rita K. ; Schneider, Michael O. ; Schoemaker, Minouk J. ; Scott, Christopher ; Shen, Chen-Yang ; Shu, Xiao-Ou ; Simard, Jaques ; Slager, Susan ; Smichkoska, Snezhana ; Southey, Melissa C. ; Spinelli, John J. ; Stone, Jennifer ; Surowy, Harald ; Swerdlow, Anthony J. ; Tamimi, Rulla M. ; Tapper, William J. ; Teo, Soo H. ; Terry, Mary Beth ; Toland, Amanda E. ; Tollenaar, Rob A. E. M. ; Torres, Diana ; Torres-Mejía, Gabriela ; Troester, Melissa A. ; Truong, Thérèse ; Tsugane, Shoichiro ; Untch, Michael ; Vachon, Celine M. ; van den Ouweland, Ans M. W. ; van Veen, Elke M. ; Vijai, Joseph ; Wendt, Camilla ; Wolk, Alicja ; Yu, Jyh-Cherng ; Zheng, Wei ; Ziogas, Argyrios ; Ziv, Elad ; Dunnig, Alison ; Pharaoh, Paul D. P. ; Schindler, Detlev ; Devilee, Peter ; Easton, Douglas F.
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Zaho, Huaying ; Ghirlando, Rodolfo ; Alfonso, Carlos ; Arisaka, Fumio ; Attali, Ilan ; Bain, David L. ; Bakhtina, Marina M. ; Becker, Donald F. ; Bedwell, Gregory J. ; Bekdemir, Ahmet ; Besong, Tabot M. D. ; Birck, Catherine ; Brautigam, Chad A. ; Brennerman, William ; Byron, Olwyn ; Bzowska, Agnieszka ; Chaires, Jonathan B. ; Chaton, Catherine T. ; Coelfen, Helmbut ; Connaghan, Keith D. ; Crowley, Kimberly A. ; Curth, Ute ; Daviter, Tina ; Dean, William L. ; Diez, Ana I. ; Ebel, Christine ; Eckert, Debra M. ; Eisele, Leslie E. ; Eisenstein, Edward ; England, Patrick ; Escalante, Carlos ; Fagan, Jeffrey A. ; Fairman, Robert ; Finn, Ron M. ; Fischle, Wolfgang ; Garcia de la Torre, Jose ; Gor, Jayesh ; Gustafsson, Henning ; Hall, Damien ; Harding, Stephen E. ; Hernandez Cifre, Jose G. ; Herr, Andrew B. ; Howell, Elizabeth E. ; Isaac, Richard S. ; Jao, Shu-Chuan ; Jose, Davis ; Kim, Soon-Jong ; Kokona, Bashkim ; Kornblatt, Jack A. ; Kosek, Dalibor ; Krayukhina, Elena ; Krzizike, Daniel ; Kusznir, Eric A. ; Kwon, Hyewon ; Larson, Adam ; Laue, Thomas M. ; Le Roy, Aline ; Leech, Andrew P. ; Lilie, Hauke ; Luger, Karolin ; Luque-Ortega, Juan R. ; Ma, Jia ; May, Carrie A. ; Maynard, Ernest L. ; Modrak-Wojcik, Anna ; Mok, Yee-Foong ; Mücke, Norbert ; Nagel-Steger, Luitgard ; Narlikar, Geeta J. ; Noda, Masanori ; Nourse, Amanda ; Obsil, Thomas ; Park, Chad K ; Park, Jin-Ku ; Pawelek, Peter D. ; Perdue, Erby E. ; Perkins, Stephen J. ; Perugini, Matthew A. ; Peterson, Craig L. ; Peverelli, Martin G. ; Piszczek, Grzegorz ; Prag, Gali ; Prevelige, Peter E. ; Raynal, Bertrand D. E. ; Rezabkova, Lenka ; Richter, Klaus ; Ringel, Alison E. ; Rosenberg, Rose ; Rowe, Arthur J. ; Rufer, Arne C. ; Scott, David J. ; Seravalli, Javier G. ; Solovyova, Alexandra S. ; Song, Renjie ; Staunton, David ; Stoddard, Caitlin ; Stott, Katherine ; Strauss, Holder M. ; Streicher, Werner W. ; Sumida, John P. ; Swygert, Sarah G. ; Szczepanowski, Roman H. ; Tessmer, Ingrid ; Toth, Ronald T. ; Tripathy, Ashutosh ; Uchiyama, Susumu ; Uebel, Stephan F. W. ; Unzai, Satoru ; Gruber, Anna Vitlin ; von Hippel, Peter H. ; Wandrey, Christine ; Wang, Szu-Huan ; Weitzel, Steven E ; Wielgus-Kutrowska, Beata ; Wolberger, Cynthia ; Wolff, Martin ; Wright, Edward ; Wu, Yu-Sung ; Wubben, Jacinta M. ; Schuck, Peter
Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304\(\pm\)0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of \(\pm\)0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies.
Ferreira, Manuel A. ; Gamazon, Eric R. ; Al-Ejeh, Fares ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arason, Adalgeir ; Arndt, Volker ; Aronson, Kristan J. ; Arun, Banu K. ; Asseryanis, Ella ; Azzollini, Jacopo ; Balmaña, Judith ; Barnes, Daniel R. ; Barrowdale, Daniel ; Beckmann, Matthias W. ; Behrens, Sabine ; Benitez, Javier ; Bermisheva, Marina ; Bialkowska, Katarzyna ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Borg, Ake ; Brauch, Hiltrud ; Brenner, Hermann ; Broeks, Annegien ; Burwinkel, Barbara ; Caldés, Trinidad ; Caligo, Maria A. ; Campa, Daniele ; Campbell, Ian ; Canzian, Federico ; Carter, Jonathan ; Carter, Brian D. ; Castelao, Jose E. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Christiansen, Hans ; Chung, Wendy K. ; Claes, Kathleen B. M. ; Clarke, Christine L. ; Couch, Fergus J. ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Daly, Mary B. ; de la Hoya, Miguel ; Dennis, Joe ; Devilee, Peter ; Diez, Orland ; Dörk, Thilo ; Dunning, Alison M. ; Dwek, Miriam ; Eccles, Diana M. ; Ejlertsen, Bent ; Ellberg, Carolina ; Engel, Christoph ; Eriksson, Mikael ; Fasching, Peter A. ; Fletcher, Olivia ; Flyger, Henrik ; Friedman, Eitan ; Frost, Debra ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Ganz, Patricia A. ; Gapstur, Susan M. ; Garber, Judy ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; Giles, Graham G. ; Glendon, Gord ; Godwin, Andrew K. ; Goldberg, Mark S. ; Goldgar, David E. ; González-Neira, Anna ; Greene, Mark H. ; Gronwald, Jacek ; Guenél, Pascal ; Haimann, Christopher A. ; Hall, Per ; Hamann, Ute ; He, Wei ; Heyworth, Jane ; Hogervorst, Frans B. L. ; Hollestelle, Antoinette ; Hoover, Robert N. ; Hopper, John L. ; Hulick, Peter J. ; Humphreys, Keith ; Imyanitov, Evgeny N. ; Isaacs, Claudine ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul A. ; Janavicius, Ramunas ; Jankowitz, Rachel C. ; John, Esther M. ; Johnson, Nichola ; Joseph, Vijai ; Karlan, Beth Y. ; Khusnutdinova, Elza ; Kiiski, Johanna I. ; Ko, Yon-Dschun ; Jones, Michael E. ; Konstantopoulou, Irene ; Kristensen, Vessela N. ; Laitman, Yael ; Lambrechts, Diether ; Lazaro, Conxi ; Leslie, Goska ; Lester, Jenny ; Lesueur, Fabienne ; Lindström, Sara ; Long, Jirong ; Loud, Jennifer T. ; Lubiński, Jan ; Makalic, Enes ; Mannermaa, Arto ; Manoochehri, Mehdi ; Margolin, Sara ; Maurer, Tabea ; Mavroudis, Dimitrios ; McGuffog, Lesley ; Meindl, Alfons ; Menon, Usha ; Michailidou, Kyriaki ; Miller, Austin ; Montagna, Marco ; Moreno, Fernando ; Moserle, Lidia ; Mulligan, Anna Marie ; Nathanson, Katherine L. ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Nevelsteen, Ines ; Nielsen, Finn C. ; Nikitina-Zake, Liene ; Nussbaum, Robert L. ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo I. ; Olsson, Håkan ; Osorio, Ana ; Papp, Janos ; Park-Simon, Tjoung-Won ; Parsons, Michael T. ; Pedersen, Inge Sokilde ; Peixoto, Ana ; Peterlongo, Paolo ; Pharaoh, Paul D. P. ; Plaseska-Karanfilska, Dijana ; Poppe, Bruce ; Presneau, Nadege ; Radice, Paolo ; Rantala, Johanna ; Rennert, Gad ; Risch, Harvey A. ; Saloustros, Emmanouil ; Sanden, Kristin ; Sawyer, Elinor J. ; Schmidt, Marjanka K. ; Schmutzler, Rita K. ; Sharma, Priyanka ; Shu, Xiao-Ou ; Simard, Jaques ; Singer, Christian F. ; Soucy, Penny ; Southey, Melissa C. ; Spinelli, John J. ; Spurdle, Amanda B. ; Stone, Jennifer ; Swerdlow, Anthony J. ; Tapper, William J. ; Taylor, Jack A. ; Teixeira, Manuel R. ; Terry, Mary Beth ; Teulé, Alex ; Thomassen, Mads ; Thöne, Kathrin ; Thull, Darcy L. ; Tischkowitz, Marc ; Toland, Amanda E. ; Torres, Diana ; Truong, Thérèse ; Tung, Nadine ; Vachon, Celine M. ; van Asperen, Christi J. ; van den Ouweland, Ans M. W. ; van Rensburg, Elizabeth J. ; Vega, Ana ; Viel, Alexandra ; Wang, Qin ; Wappenschmidt, Barbara ; Weitzel, Jeffrey N. ; Wendt, Camilla ; Winqvist, Robert ; Yang, Xiaohong R. ; Yannoukakos, Drakoulis ; Ziogas, Argyrios ; Kraft, Peter ; Antoniou, Antonis C. ; Zheng, Wei ; Easton, Douglas F. ; Milne, Roger L. ; Beesley, Jonathan ; Chenevix-Trench, Georgia
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Bousquet, Jean ; Anto, Josep M. ; Bachert, Claus ; Haahtela, Tari ; Zuberbier, Torsten ; Czarlewski, Wienczyslawa ; Bedbrook, Anna ; Bosnic‐Anticevich, Sinthia ; Walter Canonica, G. ; Cardona, Victoria ; Costa, Elisio ; Cruz, Alvaro A. ; Erhola, Marina ; Fokkens, Wytske J. ; Fonseca, Joao A. ; Illario, Maddalena ; Ivancevich, Juan‐Carlos ; Jutel, Marek ; Klimek, Ludger ; Kuna, Piotr ; Kvedariene, Violeta ; Le, LTT ; Larenas‐Linnemann, Désirée E. ; Laune, Daniel ; Lourenço, Olga M. ; Melén, Erik ; Mullol, Joaquim ; Niedoszytko, Marek ; Odemyr, Mikaëla ; Okamoto, Yoshitaka ; Papadopoulos, Nikos G. ; Patella, Vincenzo ; Pfaar, Oliver ; Pham‐Thi, Nhân ; Rolland, Christine ; Samolinski, Boleslaw ; Sheikh, Aziz ; Sofiev, Mikhail ; Suppli Ulrik, Charlotte ; Todo‐Bom, Ana ; Tomazic, Peter‐Valentin ; Toppila‐Salmi, Sanna ; Tsiligianni, Ioanna ; Valiulis, Arunas ; Valovirta, Erkka ; Ventura, Maria‐Teresa ; Walker, Samantha ; Williams, Sian ; Yorgancioglu, Arzu ; Agache, Ioana ; Akdis, Cezmi A. ; Almeida, Rute ; Ansotegui, Ignacio J. ; Annesi‐Maesano, Isabella ; Arnavielhe, Sylvie ; Basagaña, Xavier ; D. Bateman, Eric ; Bédard, Annabelle ; Bedolla‐Barajas, Martin ; Becker, Sven ; Bennoor, Kazi S. ; Benveniste, Samuel ; Bergmann, Karl C. ; Bewick, Michael ; Bialek, Slawomir ; E. Billo, Nils ; Bindslev‐Jensen, Carsten ; Bjermer, Leif ; Blain, Hubert ; Bonini, Matteo ; Bonniaud, Philippe ; Bosse, Isabelle ; Bouchard, Jacques ; Boulet, Louis‐Philippe ; Bourret, Rodolphe ; Boussery, Koen ; Braido, Fluvio ; Briedis, Vitalis ; Briggs, Andrew ; Brightling, Christopher E. ; Brozek, Jan ; Brusselle, Guy ; Brussino, Luisa ; Buhl, Roland ; Buonaiuto, Roland ; Calderon, Moises A. ; Camargos, Paulo ; Camuzat, Thierry ; Caraballo, Luis ; Carriazo, Ana‐Maria ; Carr, Warner ; Cartier, Christine ; Casale, Thomas ; Cecchi, Lorenzo ; Cepeda Sarabia, Alfonso M. ; H. Chavannes, Niels ; Chkhartishvili, Ekaterine ; Chu, Derek K. ; Cingi, Cemal ; Correia de Sousa, Jaime ; Costa, David J. ; Courbis, Anne‐Lise ; Custovic, Adnan ; Cvetkosvki, Biljana ; D'Amato, Gennaro ; da Silva, Jane ; Dantas, Carina ; Dokic, Dejan ; Dauvilliers, Yves ; De Feo, Giulia ; De Vries, Govert ; Devillier, Philippe ; Di Capua, Stefania ; Dray, Gerard ; Dubakiene, Ruta ; Durham, Stephen R. ; Dykewicz, Mark ; Ebisawa, Motohiro ; Gaga, Mina ; El‐Gamal, Yehia ; Heffler, Enrico ; Emuzyte, Regina ; Farrell, John ; Fauquert, Jean‐Luc ; Fiocchi, Alessandro ; Fink‐Wagner, Antje ; Fontaine, Jean‐François ; Fuentes Perez, José M. ; Gemicioğlu, Bilun ; Gamkrelidze, Amiran ; Garcia‐Aymerich, Judith ; Gevaert, Philippe ; Gomez, René Maximiliano ; González Diaz, Sandra ; Gotua, Maia ; Guldemond, Nick A. ; Guzmán, Maria‐Antonieta ; Hajjam, Jawad ; Huerta Villalobos, Yunuen R. ; Humbert, Marc ; Iaccarino, Guido ; Ierodiakonou, Despo ; Iinuma, Tomohisa ; Jassem, Ewa ; Joos, Guy ; Jung, Ki‐Suck ; Kaidashev, Igor ; Kalayci, Omer ; Kardas, Przemyslaw ; Keil, Thomas ; Khaitov, Musa ; Khaltaev, Nikolai ; Kleine‐Tebbe, Jorg ; Kouznetsov, Rostislav ; Kowalski, Marek L. ; Kritikos, Vicky ; Kull, Inger ; La Grutta, Stefania ; Leonardini, Lisa ; Ljungberg, Henrik ; Lieberman, Philip ; Lipworth, Brian ; Lodrup Carlsen, Karin C. ; Lopes‐Pereira, Catarina ; Loureiro, Claudia C. ; Louis, Renaud ; Mair, Alpana ; Mahboub, Bassam ; Makris, Michaël ; Malva, Joao ; Manning, Patrick ; Marshall, Gailen D. ; Masjedi, Mohamed R. ; Maspero, Jorge F. ; Carreiro‐Martins, Pedro ; Makela, Mika ; Mathieu‐Dupas, Eve ; Maurer, Marcus ; De Manuel Keenoy, Esteban ; Melo‐Gomes, Elisabete ; Meltzer, Eli O. ; Menditto, Enrica ; Mercier, Jacques ; Micheli, Yann ; Miculinic, Neven ; Mihaltan, Florin ; Milenkovic, Branislava ; Mitsias, Dimitirios I. ; Moda, Giuliana ; Mogica‐Martinez, Maria‐Dolores ; Mohammad, Yousser ; Montefort, Steve ; Monti, Ricardo ; Morais‐Almeida, Mario ; Mösges, Ralph ; Münter, Lars ; Muraro, Antonella ; Murray, Ruth ; Naclerio, Robert ; Napoli, Luigi ; Namazova‐Baranova, Leyla ; Neffen, Hugo ; Nekam, Kristoff ; Neou, Angelo ; Nordlund, Björn ; Novellino, Ettore ; Nyembue, Dieudonné ; O'Hehir, Robyn ; Ohta, Ken ; Okubo, Kimi ; Onorato, Gabrielle L. ; Orlando, Valentina ; Ouedraogo, Solange ; Palamarchuk, Julia ; Pali‐Schöll, Isabella ; Panzner, Peter ; Park, Hae‐Sim ; Passalacqua, Gianni ; Pépin, Jean‐Louis ; Paulino, Ema ; Pawankar, Ruby ; Phillips, Jim ; Picard, Robert ; Pinnock, Hilary ; Plavec, Davor ; Popov, Todor A. ; Portejoie, Fabienne ; Price, David ; Prokopakis, Emmanuel P. ; Psarros, Fotis ; Pugin, Benoit ; Puggioni, Francesca ; Quinones‐Delgado, Pablo ; Raciborski, Filip ; Rajabian‐Söderlund, Rojin ; Regateiro, Frederico S. ; Reitsma, Sietze ; Rivero‐Yeverino, Daniela ; Roberts, Graham ; Roche, Nicolas ; Rodriguez‐Zagal, Erendira ; Rolland, Christine ; Roller‐Wirnsberger, Regina E. ; Rosario, Nelson ; Romano, Antonino ; Rottem, Menachem ; Ryan, Dermot ; Salimäki, Johanna ; Sanchez‐Borges, Mario M. ; Sastre, Joaquin ; Scadding, Glenis K. ; Scheire, Sophie ; Schmid‐Grendelmeier, Peter ; Schünemann, Holger J. ; Sarquis Serpa, Faradiba ; Shamji, Mohamed ; Sisul, Juan‐Carlos ; Sofiev, Mikhail ; Solé, Dirceu ; Somekh, David ; Sooronbaev, Talant ; Sova, Milan ; Spertini, François ; Spranger, Otto ; Stellato, Cristiana ; Stelmach, Rafael ; Thibaudon, Michel ; To, Teresa ; Toumi, Mondher ; Usmani, Omar ; Valero, Antonio A. ; Valenta, Rudolph ; Valentin‐Rostan, Marylin ; Pereira, Marilyn Urrutia ; van der Kleij, Rianne ; Van Eerd, Michiel ; Vandenplas, Olivier ; Vasankari, Tuula ; Vaz Carneiro, Antonio ; Vezzani, Giorgio ; Viart, Frédéric ; Viegi, Giovanni ; Wallace, Dana ; Wagenmann, Martin ; Wang, De Yun ; Waserman, Susan ; Wickman, Magnus ; Williams, Dennis M. ; Wong, Gary ; Wroczynski, Piotr ; Yiallouros, Panayiotis K. ; Yusuf, Osman M. ; Zar, Heather J. ; Zeng, Stéphane ; Zernotti, Mario E. ; Zhang, Luo ; Shan Zhong, Nan ; Zidarn, Mihaela
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
El-Helou, Sabine M. ; Biegner, Anika-Kerstin ; Bode, Sebastian ; Ehl, Stephan R. ; Heeg, Maximilian ; Maccari, Maria E. ; Ritterbusch, Henrike ; Speckmann, Carsten ; Rusch, Stephan ; Scheible, Raphael ; Warnatz, Klaus ; Atschekzei, Faranaz ; Beider, Renata ; Ernst, Diana ; Gerschmann, Stev ; Jablonka, Alexandra ; Mielke, Gudrun ; Schmidt, Reinhold E. ; Schürmann, Gesine ; Sogkas, Georgios ; Baumann, Ulrich H. ; Klemann, Christian ; Viemann, Dorothee ; Bernuth, Horst von ; Krüger, Renate ; Hanitsch, Leif G. ; Scheibenbogen, Carmen M. ; Wittke, Kirsten ; Albert, Michael H. ; Eichinger, Anna ; Hauck, Fabian ; Klein, Christoph ; Rack-Hoch, Anita ; Sollinger, Franz M. ; Avila, Anne ; Borte, Michael ; Borte, Stephan ; Fasshauer, Maria ; Hauenherm, Anja ; Kellner, Nils ; Müller, Anna H. ; Ülzen, Anett ; Bader, Peter ; Bakhtiar, Shahrzad ; Lee, Jae-Yun ; Heß, Ursula ; Schubert, Ralf ; Wölke, Sandra ; Zielen, Stefan ; Ghosh, Sujal ; Laws, Hans-Juergen ; Neubert, Jennifer ; Oommen, Prasad T. ; Hönig, Manfred ; Schulz, Ansgar ; Steinmann, Sandra ; Klaus, Schwarz ; Dückers, Gregor ; Lamers, Beate ; Langemeyer, Vanessa ; Niehues, Tim ; Shai, Sonu ; Graf, Dagmar ; Müglich, Carmen ; Schmalzing, Marc T. ; Schwaneck, Eva C. ; Tony, Hans-Peter ; Dirks, Johannes ; Haase, Gabriele ; Liese, Johannes G. ; Morbach, Henner ; Foell, Dirk ; Hellige, Antje ; Wittkowski, Helmut ; Masjosthusmann, Katja ; Mohr, Michael ; Geberzahn, Linda ; Hedrich, Christian M. ; Müller, Christiane ; Rösen-Wolff, Angela ; Roesler, Joachim ; Zimmermann, Antje ; Behrends, Uta ; Rieber, Nikolaus ; Schauer, Uwe ; Handgretinger, Rupert ; Holzer, Ursula ; Henes, Jörg ; Kanz, Lothar ; Boesecke, Christoph ; Rockstroh, Jürgen K. ; Schwarze-Zander, Carolynne ; Wasmuth, Jan-Christian ; Dilloo, Dagmar ; Hülsmann, Brigitte ; Schönberger, Stefan ; Schreiber, Stefan ; Zeuner, Rainald ; Ankermann, Tobias ; Bismarck, Philipp von ; Huppertz, Hans-Iko ; Kaiser-Labusch, Petra ; Greil, Johann ; Jakoby, Donate ; Kulozik, Andreas E. ; Metzler, Markus ; Naumann-Bartsch, Nora ; Sobik, Bettina ; Graf, Norbert ; Heine, Sabine ; Kobbe, Robin ; Lehmberg, Kai ; Müller, Ingo ; Herrmann, Friedrich ; Horneff, Gerd ; Klein, Ariane ; Peitz, Joachim ; Schmidt, Nadine ; Bielack, Stefan ; Groß-Wieltsch, Ute ; Classen, Carl F. ; Klasen, Jessica ; Deutz, Peter ; Kamitz, Dirk ; Lassy, Lisa ; Tenbrock, Klaus ; Wagner, Norbert ; Bernbeck, Benedikt ; Brummel, Bastian ; Lara-Villacanas, Eusebia ; Münstermann, Esther ; Schneider, Dominik T. ; Tietsch, Nadine ; Westkemper, Marco ; Weiß, Michael ; Kramm, Christof ; Kühnle, Ingrid ; Kullmann, Silke ; Girschick, Hermann ; Specker, Christof ; Vinnemeier-Laubenthal, Elisabeth ; Haenicke, Henriette ; Schulz, Claudia ; Schweigerer, Lothar ; Müller, Thomas G. ; Stiefel, Martina ; Belohradsky, Bernd H. ; Soetedjo, Veronika ; Kindle, Gerhard ; Grimbacher, Bodo
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Galluzzi, L. ; Bravo-San Pedro, J. M. ; Vitale, I. ; Aaronson, S. A. ; Abrams, J. M. ; Adam, D. ; Alnemri, E. S. ; Altucci, L. ; Andrews, D. ; Annicchiarico-Petruzelli, M. ; Baehrecke, E. H. ; Bazan, N. G. ; Bertrand, M. J. ; Bianchi, K. ; Blagosklonny, M. V. ; Blomgren, K. ; Borner, C. ; Bredesen, D. E. ; Brenner, C. ; Campanella, M. ; Candi, E. ; Cecconi, F. ; Chan, F. K. ; Chandel, N. S. ; Cheng, E. H. ; Chipuk, J. E. ; Cidlowski, J. A. ; Ciechanover, A. ; Dawson, T. M. ; Dawson, V. L. ; De Laurenzi, V. ; De Maria, R. ; Debatin, K. M. ; Di Daniele, N. ; Dixit, V. M. ; Dynlacht, B. D. ; El-Deiry, W. S. ; Fimia, G. M. ; Flavell, R. A. ; Fulda, S. ; Garrido, C. ; Gougeon, M. L. ; Green, D. R. ; Gronemeyer, H. ; Hajnoczky, G. ; Hardwick, J. M. ; Hengartner, M. O. ; Ichijo, H. ; Joseph, B. ; Jost, P. J. ; Kaufmann, T. ; Kepp, O. ; Klionsky, D. J. ; Knight, R. A. ; Kumar, S. ; Lemasters, J. J. ; Levine, B. ; Linkermann, A. ; Lipton, S. A. ; Lockshin, R. A. ; López-Otín, C. ; Lugli, E. ; Madeo, F. ; Malorni, W. ; Marine, J. C. ; Martin, S. J. ; Martinou, J. C. ; Medema, J. P. ; Meier, P. ; Melino, S. ; Mizushima, N. ; Moll, U. ; Muñoz-Pinedo, C. ; Nuñez, G. ; Oberst, A. ; Panaretakis, T. ; Penninger, J. M. ; Peter, M. E. ; Piacentini, M. ; Pinton, P. ; Prehn, J. H. ; Puthalakath, H. ; Rabinovich, G. A. ; Ravichandran, K. S. ; Rizzuto, R. ; Rodrigues, C. M. ; Rubinsztein, D. C. ; Rudel, T. ; Shi, Y. ; Simon, H. U. ; Stockwell, B. R. ; Szabadkai, G. ; Tait, S. W. ; Tang, H. L. ; Tavernarakis, N. ; Tsujimoto, Y. ; Vanden Berghe, T. ; Vandenabeele, P. ; Villunger, A. ; Wagner, E. F. ; Walczak, H. ; White, E. ; Wood, W. G. ; Yuan, J. ; Zakeri, Z. ; Zhivotovsky, B. ; Melino, G. ; Kroemer, G.
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Dumont, Martine ; Weber-Lassalle, Nana ; Joly-Beauparlant, Charles ; Ernst, Corinna ; Droit, Arnaud ; Feng, Bing-Jian ; Dubois, Stéphane ; Collin-Deschesnes, Annie-Claude ; Soucy, Penny ; Vallée, Maxime ; Fournier, Frédéric ; Lemaçon, Audrey ; Adank, Muriel A. ; Allen, Jamie ; Altmüller, Janine ; Arnold, Norbert ; Ausems, Margreet G. E. M. ; Berutti, Riccardo ; Bolla, Manjeet K. ; Bull, Shelley ; Carvalho, Sara ; Cornelissen, Sten ; Dufault, Michael R. ; Dunning, Alison M. ; Engel, Christoph ; Gehrig, Andrea ; Geurts-Giele, Willemina R. R. ; Gieger, Christian ; Green, Jessica ; Hackmann, Karl ; Helmy, Mohamed ; Hentschel, Julia ; Hogervorst, Frans B. L. ; Hollestelle, Antoinette ; Hooning, Maartje J. ; Horváth, Judit ; Ikram, M. Arfan ; Kaulfuß, Silke ; Keeman, Renske ; Kuang, Da ; Luccarini, Craig ; Maier, Wolfgang ; Martens, John W. M. ; Niederacher, Dieter ; Nürnberg, Peter ; Ott, Claus-Eric ; Peters, Annette ; Pharoah, Paul D. P. ; Ramirez, Alfredo ; Ramser, Juliane ; Riedel-Heller, Steffi ; Schmidt, Gunnar ; Shah, Mitul ; Scherer, Martin ; Stäbler, Antje ; Strom, Tim M. ; Sutter, Christian ; Thiele, Holger ; van Asperen, Christi J. ; van der Kolk, Lizet ; van der Luijt, Rob B. ; Volk, Alexander E. ; Wagner, Michael ; Waisfisz, Quinten ; Wang, Qin ; Wang-Gohrke, Shan ; Weber, Bernhard H. F. ; Devilee, Peter ; Tavtigian, Sean ; Bader, Gary D. ; Meindl, Alfons ; Goldgar, David E. ; Andrulis, Irene L. ; Schmutzler, Rita K. ; Easton, Douglas F. ; Schmidt, Marjanka K. ; Hahnen, Eric ; Simard, Jacques
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
Couch, Fergus J. ; Wang, Xianshu ; McGuffog, Lesley ; Lee, Andrew ; Olswold, Curtis ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Fredericksen, Zachary ; Barrowdale, Daniel ; Dennis, Joe ; Gaudet, Mia M. ; Dicks, Ed ; Kosel, Matthew ; Healey, Sue ; Sinilnikova, Olga M. ; Lee, Adam ; Bacot, Françios ; Vincent, Daniel ; Hogervorst, Frans B. L. ; Peock, Susan ; Stoppa-Lyonnet, Dominique ; Jakubowska, Anna ; Radice, Paolo ; Schmutzler, Rita Katharina ; Domchek, Susan M. ; Piedmonte, Marion ; Singer, Christian F. ; Friedman, Eitan ; Thomassen, Mads ; Hansen, Thomas V. O. ; Neuhausen, Susan L. ; Szabo, Csilla I. ; Blanco, Ingnacio ; Greene, Mark H. ; Karlan, Beth Y. ; Garber, Judy ; Phelan, Catherine M. ; Weitzel, Jeffrey N. ; Montagna, Marco ; Olah, Edith ; Andrulis, Irene L. ; Godwin, Andrew K. ; Yannoukakos, Drakoulis ; Goldgar, David E. ; Caldes, Trinidad ; Nevanlinna, Heli ; Osorio, Ana ; Terry, Mary Beth ; Daly, Mary B. ; van Rensburg, Elisabeth J. ; Hamann, Ute ; Ramus, Susan J. ; Toland, Amanda Ewart ; Caligo, Maria A. ; Olopade, Olufunmilayo I. ; Tung, Nadine ; Claes, Kathleen ; Beattie, Mary S. ; Southey, Melissa C. ; Imyanitov, Evgeny N. ; Tischkowitz, Marc ; Janavicius, Ramunas ; John, Esther M. ; Kwong, Ava ; Diez, Orland ; Kwong, Ava ; Balmaña, Judith ; Barkardottir, Rosa B. ; Arun, Banu K. ; Rennert, Gad ; Teo, Soo-Hwang ; Ganz, Patricia A. ; Campbell, Ian ; van der Hout, Annemarie H. ; van Deurzen, Carolien H. M. ; Seynaeve, Caroline ; Garcia, Encarna B. Gómez ; van Leeuwen, Flora E. ; Meijers-Heijboer, Hanne E. J. ; Gille, Johannes J. P. ; Ausems, Magreet G. E. M. ; Blok, Marinus J. ; Ligtenberg, Marjolinjin J. L. ; Rookus, Matti A. ; Devilee, Peter ; Verhoef, Senno ; van Os, Theo A. M. ; Wijnen, Juul T. ; Frost, Debra ; Ellis, Steve ; Fineberg, Elena ; Platte, Radke ; Evans, D. Gareth ; Izatt, Luise ; Eeles, Rosalind A. ; Adlard, Julian ; Eccles, Diana M. ; Cook, Jackie ; Brewer, Carole ; Douglas, Fiona ; Hodgson, Shirley ; Morrison, Patrick J. ; Side, Lucy E. ; Donaldson, Alan ; Houghton, Catherine ; Rogers, Mark T. ; Dorkins, Huw ; Eason, Jacqueline ; Gregory, Helen ; McCann, Emma ; Murray, Alex ; Calender, Alain ; Hardouin, Agnès ; Berthet, Pascaline ; Delnatte, Capucine ; Nogues, Catherine ; Lasset, Christine ; Houdayer, Claude ; Leroux,, Dominique ; Rouleau, Etienne ; Prieur, Fabienne ; Damiola, Francesca ; Sobol, Hagay ; Coupier, Isabelle ; Venat-Bouvet, Laurence ; Castera, Laurent ; Gauthier-Villars, Marion ; Léoné, Mélanie ; Pujol, Pascal ; Mazoyer, Sylvie ; Bignon, Yves-Jean ; Zlowocka-Perlowska, Elzbieta ; Gronwald, Jacek ; Lubinski,, Jan ; Durda, Katarzyna ; Jaworska, Katarzyna ; Huzarski, Tomasz ; Spurdle, Amanda B. ; Viel, Alessandra ; Peissel, Bernhard ; Bonanni, Bernardo ; Melloni, Guilia ; Ottini, Laura ; Papi, Laura ; Varesco, Liliana ; Tibiletti, Maria Grazia ; Peterlongo, Paolo ; Volorio, Sara ; Manoukian, Siranoush ; Pensotti, Valeria ; Arnold, Norbert ; Engel, Christoph ; Deissler, Helmut ; Gadzicki, Dorothea ; Gehrig, Andrea ; Kast, Karin ; Rhiem, Kerstin ; Meindl, Alfons ; Niederacher, Dieter ; Ditsch, Nina ; Plendl, Hansjoerg ; Preisler-Adams, Sabine ; Engert, Stefanie ; Sutter, Christian ; Varon-Mateeva, Raymenda ; Wappenschmidt, Barbara ; Weber, Bernhard H. F. ; Arver, Brita ; Stenmark-Askmalm, Marie ; Loman, Niklas ; Rosenquist, Richard ; Einbeigi, Zakaria ; Nathanson, Katherine L. ; Rebbeck, Timothy R. ; Blank, Stephanie V. ; Cohn, David E. ; Rodriguez, Gustavo C. ; Small, Laurie ; Friedlander, Michael ; Bae-Jump, Victoria L. ; Fink-Retter, Anneliese ; Rappaport, Christine ; Gschwantler-Kaulich, Daphne ; Pfeiler, Georg ; Tea, Muy-Kheng ; Lindor, Noralane M. ; Kaufman, Bella ; Paluch, Shani Shimon ; Laitman, Yael ; Skytte, Anne-Bine ; Gerdes, Anne-Marie ; Pedersen, Inge Sokilde ; Moeller, Sanne Traasdahl ; Kruse, Torben A. ; Jensen, Uffe Birk ; Vijai, Joseph ; Sarrel, Kara ; Robson, Mark ; Kauff, Noah ; Mulligan, Anna Marie ; Glendon, Gord ; Ozcelik, Hilmi ; Ejlertsen, Bent ; Nielsen, Finn C. ; Jønson, Lars ; Andersen, Mette K. ; Ding, Yuan Chun ; Steele, Linda ; Foretova, Lenka ; Teulé, Alex ; Lazaro, Conxi ; Brunet, Joan ; Pujana, Miquel Angel ; Mai, Phuong L. ; Loud, Jennifer T. ; Walsh, Christine ; Lester, Jenny ; Orsulic, Sandra ; Narod, Steven A. ; Herzog, Josef ; Sand, Sharon R. ; Tognazzo, Silvia ; Agata, Simona ; Vaszko, Tibor ; Weaver, Joellen ; Stravropoulou, Alexandra V. ; Buys, Saundra S. ; Romero, Atocha ; de la Hoya, Miguel ; Aittomäki, Kristiina ; Muranen, Taru A. ; Duran, Mercedes ; Chung, Wendy K. ; Lasa, Adriana ; Dorfling, Cecilia M. ; Miron, Alexander ; Benitez, Javier ; Senter, Leigha ; Huo, Dezheng ; Chan, Salina B. ; Sokolenko, Anna P. ; Chiquette, Jocelyne ; Tihomirova, Laima ; Friebel, Tara M. ; Agnarsson, Bjarne A. ; Lu, Karen H. ; Lejbkowicz, Flavio ; James, Paul A. ; Hall, Per ; Dunning, Alison M. ; Tessier, Daniel ; Cunningham, Julie ; Slager, Susan L. ; Chen, Wang ; Hart, Steven ; Stevens, Kristen ; Simard, Jacques ; Pastinen, Tomi ; Pankratz, Vernon S. ; Offit, Kenneth ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Blein, Sophie ; Bardel, Claire ; Danjean, Vincent ; McGuffog, Lesley ; Healay, Sue ; Barrowdale, Daniel ; Lee, Andrew ; Dennis, Joe ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Terry, Mary Beth ; Chung, Wendy K. ; Goldgar, David E. ; Buys, Saundra S. ; Janavicius, Ramunas ; Tihomirova, Laima ; Tung, Nadine ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Gerdes, Anne-Marie ; Ejlertsen, Bent ; Nielsen, Finn C. ; Hansen, Thomas V. O. ; Osorio, Ana ; Benitez, Javier ; Andreas Conejero, Raquel ; Segota, Ena ; Weitzel, Jeffrey N. ; Thelander, Margo ; Peterlongo, Paolo ; Radice, Paolo ; Pensotti, Valeria ; Dolcetti, Riccardo ; Bonanni, Bernardo ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Giulietta ; Manoukian, Siranoush ; Varesco, Liliana ; Capone, Gabriele L. ; Papi, Laura ; Ottini, Laura ; Yannoukakos, Drakoulis ; Konstantopoulou, Irene ; Garber, Judy ; Hamann, Ute ; Donaldson, Alan ; Brady, Angela ; Brewer, Carole ; Foo, Claire ; Evans, D. Gareth ; Frost, Debra ; Eccles, Diana ; Douglas, Fiona ; Cook, Jackie ; Adlard, Julian ; Barwell, Julian ; Walker, Lisa ; Izatt, Louise ; Side, Lucy E. ; Kennedy, M. John ; Tischkowitz, Marc ; Rogers, Mark T. ; Porteous, Mary E. ; Morrison, Patrick J. ; Platte, Radka ; Eeles, Ros ; Davidson, Rosemarie ; Hodgson, Shirley ; Cole, Trevor ; Godwin, Andrew K ; Isaacs, Claudine ; Claes, Kathleen ; De Leeneer, Kim ; Meindl, Alfons ; Gehrig, Andrea ; Wappenschmidt, Barbara ; Sutter, Christian ; Engel, Christoph ; Niederacher, Dieter ; Steinemann, Doris ; Plendl, Hansjoerg ; Kast, Karin ; Rhiem, Kerstin ; Ditsch, Nina ; Arnold, Norbert ; Varon-Mateeva, Raymonda ; Schmutzler, Rita K. ; Preisler-Adams, Sabine ; Markov, Nadja Bogdanova ; Wang-Gohrke, Shan ; de Pauw, Antoine ; Lefol, Cedrick ; Lasset, Christine ; Leroux, Dominique ; Rouleau, Etienne ; Damiola, Francesca ; Dreyfus, Helene ; Barjhoux, Laure ; Golmard, Lisa ; Uhrhammer, Nancy ; Bonadona, Valerie ; Sornin, Valerie ; Bignon, Yves-Jean ; Carter, Jonathan ; Van Le, Linda ; Piedmonte, Marion ; DiSilvestro, Paul A. ; de la Hoya, Miguel ; Caldes, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Jager, Agnes ; van den Ouweland, Ans M. W. ; Kets, Carolien M. ; Aalfs, Cora M. ; van Leeuwen, Flora E. ; Hogervorst, Frans B. L. ; Meijers-Heijboer, Hanne E. J. ; Oosterwijk, Jan C. ; van Roozendaal, Kees E. P. ; Rookus, Matti A. ; Devilee, Peter ; van der Luijt, Rob B. ; Olah, Edith ; Diez, Orland ; Teule, Alex ; Lazaro, Conxi ; Blanco, Ignacio ; Del Valle, Jesus ; Jakubowska, Anna ; Sukiennicki, Grzegorz ; Gronwald, Jacek ; Spurdle, Amanda B. ; Foulkes, William ; Olswold, Curtis ; Lindor, Noralene M. ; Pankratz, Vernon S. ; Szabo, Csilla I. ; Lincoln, Anne ; Jacobs, Lauren ; Corines, Marina ; Robson, Mark ; Vijai, Joseph ; Berger, Andreas ; Fink-Retter, Anneliese ; Singer, Christian F. ; Rappaport, Christine ; Geschwantler Kaulich, Daphne ; Pfeiler, Georg ; Tea, Muy-Kheng ; Greene, Mark H. ; Mai, Phuong L. ; Rennert, Gad ; Imyanitov, Evgeny N. ; Mulligan, Anna Marie ; Glendon, Gord ; Andrulis, Irene L. ; Tchatchou, Andrine ; Toland, Amanda Ewart ; Pedersen, Inge Sokilde ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Caligo, Maria A. ; Friedman, Eitan ; Zidan, Jamal ; Laitman, Yael ; Lindblom, Annika ; Melin, Beatrice ; Arver, Brita ; Loman, Niklas ; Rosenquist, Richard ; Olopade, Olufunmilayo I. ; Nussbaum, Robert L. ; Ramus, Susan J. ; Nathanson, Katherine L. ; Domchek, Susan M. ; Rebbeck, Timothy R. ; Arun, Banu K. ; Mitchell, Gillian ; Karlan, Bethy Y. ; Lester, Jenny ; Orsulic, Sandra ; Stoppa-Lyonnet, Dominique ; Thomas, Gilles ; Simard, Jacques ; Couch, Fergus J. ; Offit, Kenenth ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Mazoyer, Sylvie ; Phelan, Catherine M. ; Sinilnikova, Olga M. ; Cox, David G.
Introduction:
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods:
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results:
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions:
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Hudson, Lawrence N. ; Newbold, Tim ; Contu, Sara ; Hill, Samantha L. L. ; Lysenko, Igor ; De Palma, Adriana ; Phillips, Helen R. P. ; Senior, Rebecca A. ; Bennett, Dominic J. ; Booth, Hollie ; Choimes, Argyrios ; Correia, David L. P. ; Day, Julie ; Echeverria-Londono, Susy ; Garon, Morgan ; Harrison, Michelle L. K. ; Ingram, Daniel J. ; Jung, Martin ; Kemp, Victoria ; Kirkpatrick, Lucinda ; Martin, Callum D. ; Pan, Yuan ; White, Hannah J. ; Aben, Job ; Abrahamczyk, Stefan ; Adum, Gilbert B. ; Aguilar-Barquero, Virginia ; Aizen, Marcelo ; Ancrenaz, Marc ; Arbelaez-Cortes, Enrique ; Armbrecht, Inge ; Azhar, Badrul ; Azpiroz, Adrian B. ; Baeten, Lander ; Báldi, András ; Banks, John E. ; Barlow, Jos ; Batáry, Péter ; Bates, Adam J. ; Bayne, Erin M. ; Beja, Pedro ; Berg, Ake ; Berry, Nicholas J. ; Bicknell, Jake E. ; Bihn, Jochen H. ; Böhning-Gaese, Katrin ; Boekhout, Teun ; Boutin, Celine ; Bouyer, Jeremy ; Brearley, Francis Q. ; Brito, Isabel ; Brunet, Jörg ; Buczkowski, Grzegorz ; Buscardo, Erika ; Cabra-Garcia, Jimmy ; Calvino-Cancela, Maria ; Cameron, Sydney A. ; Cancello, Eliana M. ; Carrijo, Tiago F. ; Carvalho, Anelena L. ; Castro, Helena ; Castro-Luna, Alejandro A. ; Cerda, Rolando ; Cerezo, Alexis ; Chauvat, Matthieu ; Clarke, Frank M. ; Cleary, Daniel F. R. ; Connop, Stuart P. ; D'Aniello, Biagio ; da Silva, Pedro Giovani ; Darvill, Ben ; Dauber, Jens ; Dejean, Alain ; Diekötter, Tim ; Dominguez-Haydar, Yamileth ; Dormann, Carsten F. ; Dumont, Bertrand ; Dures, Simon G. ; Dynesius, Mats ; Edenius, Lars ; Elek, Zoltán ; Entling, Martin H. ; Farwig, Nina ; Fayle, Tom M. ; Felicioli, Antonio ; Felton, Annika M. ; Ficetola, Gentile F. ; Filgueiras, Bruno K. C. ; Fonte, Steve J. ; Fraser, Lauchlan H. ; Fukuda, Daisuke ; Furlani, Dario ; Ganzhorn, Jörg U. ; Garden, Jenni G. ; Gheler-Costa, Carla ; Giordani, Paolo ; Giordano, Simonetta ; Gottschalk, Marco S. ; Goulson, Dave ; Gove, Aaron D. ; Grogan, James ; Hanley, Mick E. ; Hanson, Thor ; Hashim, Nor R. ; Hawes, Joseph E. ; Hébert, Christian ; Helden, Alvin J. ; Henden, John-André ; Hernández, Lionel ; Herzog, Felix ; Higuera-Diaz, Diego ; Hilje, Branko ; Horgan, Finbarr G. ; Horváth, Roland ; Hylander, Kristoffer ; Horváth, Roland ; Isaacs-Cubides, Paola ; Ishitani, Mashiro ; Jacobs, Carmen T. ; Jaramillo, Victor J. ; Jauker, Birgit ; Jonsell, Matts ; Jung, Thomas S. ; Kapoor, Vena ; Kati, Vassiliki ; Katovai, Eric ; Kessler, Michael ; Knop, Eva ; Kolb, Annette ; Körösi, Àdám ; Lachat, Thibault ; Lantschner, Victoria ; Le Féon, Violette ; LeBuhn, Gretchen ; Légaré, Jean-Philippe ; Letcher, Susan G. ; Littlewood, Nick A. ; López-Quintero, Carlos A. ; Louhaichi, Mounir ; Lövei, Gabor L. ; Lucas-Borja, Manuel Esteban ; Luja, Victor H. ; Maeto, Kaoru ; Magura, Tibor ; Mallari, Neil Aldrin ; Marin-Spiotta, Erika ; Marhall, E. J. P. ; Martínez, Eliana ; Mayfield, Margaret M. ; Mikusinski, Gregorz ; Milder, Jeffery C. ; Miller, James R. ; Morales, Carolina L. ; Muchane, Mary N. ; Muchane, Muchai ; Naidoo, Robin ; Nakamura, Akihiro ; Naoe, Shoji ; Nates-Parra, Guiomar ; Navarerete Gutierrez, Dario A. ; Neuschulz, Eike L. ; Noreika, Norbertas ; Norfolk, Olivia ; Noriega, Jorge Ari ; Nöske, Nicole M. ; O'Dea, Niall ; Oduro, William ; Ofori-Boateng, Caleb ; Oke, Chris O. ; Osgathorpe, Lynne M. ; Paritsis, Juan ; Parrah, Alejandro ; Pelegrin, Nicolás ; Peres, Carlos A. ; Persson, Anna S. ; Petanidou, Theodora ; Phalan, Ben ; Philips, T. Keith ; Poveda, Katja ; Power, Eileen F. ; Presley, Steven J. ; Proença, Vânia ; Quaranta, Marino ; Quintero, Carolina ; Redpath-Downing, Nicola A. ; Reid, J. Leighton ; Reis, Yana T. ; Ribeiro, Danilo B. ; Richardson, Barbara A. ; Richardson, Michael J. ; Robles, Carolina A. ; Römbke, Jörg ; Romero-Duque, Luz Piedad ; Rosselli, Loreta ; Rossiter, Stephen J. ; Roulston, T'ai H. ; Rousseau, Laurent ; Sadler, Jonathan P. ; Sáfián, Szbolcs ; Saldaña-Vásquez, Romeo A. ; Samnegård, Ulrika ; Schüepp, Christof ; Schweiger, Oliver ; Sedlock, Jodi L. ; Shahabuddin, Ghazala ; Sheil, Douglas ; Silva, Fernando A. B. ; Slade, Eleanor ; Smith-Pardo, Allan H. ; Sodhi, Navjot S. ; Somarriba, Eduardo J. ; Sosa, Ramón A. ; Stout, Jane C. ; Struebig, Matthew J. ; Sung, Yik-Hei ; Threlfall, Caragh G. ; Tonietto, Rebecca ; Tóthmérész, Béla ; Tscharntke, Teja ; Turner, Edgar C. ; Tylianakis, Jason M. ; Vanbergen, Adam J. ; Vassilev, Kiril ; Verboven, Hans A. F. ; Vergara, Carlos H. ; Vergara, Pablo M. ; Verhulst, Jort ; Walker, Tony R. ; Wang, Yanping ; Watling, James I. ; Wells, Konstans ; Williams, Christopher D. ; Willig, Michael R. ; Woinarski, John C. Z. ; Wolf, Jan H. D. ; Woodcock, Ben A. ; Yu, Douglas W. ; Zailsev, Andreys ; Collen, Ben ; Ewers, Rob M. ; Mace, Georgina M. ; Purves, Drew W. ; Scharlemann, Jörn P. W. ; Pervis, Andy
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.