TY  - JOUR
A1  - Vigorito, Elena
A1  - Kuchenbaecker, Karoline B.
A1  - Beesley, Jonathan
A1  - Adlard, Julian
A1  - Agnarsson, Bjarni A.
A1  - Andrulis, Irene L.
A1  - Arun, Banu K.
A1  - Barjhoux, Laure
A1  - Belotti, Muriel
A1  - Benitez, Javier
A1  - Berger, Andreas
A1  - Bojesen, Anders
A1  - Bonanni, Bernardo
A1  - Brewer, Carole
A1  - Caldes, Trinidad
A1  - Caligo, Maria A.
A1  - Campbell, Ian
A1  - Chan, Salina B.
A1  - Claes, Kathleen B. M.
A1  - Cohn, David E.
A1  - Cook, Jackie
A1  - Daly, Mary B.
A1  - Damiola, Francesca
A1  - Davidson, Rosemarie
A1  - de Pauw, Antoine
A1  - Delnatte, Capucine
A1  - Diez, Orland
A1  - Domchek, Susan M.
A1  - Dumont, Martine
A1  - Durda, Katarzyna
A1  - Dworniczak, Bernd
A1  - Easton, Douglas F.
A1  - Eccles, Diana
A1  - Ardnor, Christina Edwinsdotter
A1  - Eeles, Ros
A1  - Ejlertsen, Bent
A1  - Ellis, Steve
A1  - Evans, D. Gareth
A1  - Feliubadalo, Lidia
A1  - Fostira, Florentia
A1  - Foulkes, William D.
A1  - Friedman, Eitan
A1  - Frost, Debra
A1  - Gaddam, Pragna
A1  - Ganz, Patricia A.
A1  - Garber, Judy
A1  - Garcia-Barberan, Vanesa
A1  - Gauthier-Villars, Marion
A1  - Gehrig, Andrea
A1  - Gerdes, Anne-Marie
A1  - Giraud, Sophie
A1  - Godwin, Andrew K.
A1  - Goldgar, David E.
A1  - Hake, Christopher R.
A1  - Hansen, Thomas V. O.
A1  - Healey, Sue
A1  - Hodgson, Shirley
A1  - Hogervorst, Frans B. L.
A1  - Houdayer, Claude
A1  - Hulick, Peter J.
A1  - Imyanitov, Evgeny N.
A1  - Isaacs, Claudine
A1  - Izatt, Louise
A1  - Izquierdo, Angel
A1  - Jacobs, Lauren
A1  - Jakubowska, Anna
A1  - Janavicius, Ramunas
A1  - Jaworska-Bieniek, Katarzyna
A1  - Jensen, Uffe Birk
A1  - John, Esther M.
A1  - Vijai, Joseph
A1  - Karlan, Beth Y.
A1  - Kast, Karin
A1  - Khan, Sofia
A1  - Kwong, Ava
A1  - Laitman, Yael
A1  - Lester, Jenny
A1  - Lesueur, Fabienne
A1  - Liljegren, Annelie
A1  - Lubinski, Jan
A1  - Mai, Phuong L.
A1  - Manoukian, Siranoush
A1  - Mazoyer, Sylvie
A1  - Meindl, Alfons
A1  - Mensenkamp, Arjen R.
A1  - Montagna, Marco
A1  - Nathanson, Katherine L.
A1  - Neuhausen, Susan L.
A1  - Nevanlinna, Heli
A1  - Niederacher, Dieter
A1  - Olah, Edith
A1  - Olopade, Olufunmilayo I.
A1  - Ong, Kai-ren
A1  - Osorio, Ana
A1  - Park, Sue Kyung
A1  - Paulsson-Karlsson, Ylva
A1  - Pedersen, Inge Sokilde
A1  - Peissel, Bernard
A1  - Peterlongo, Paolo
A1  - Pfeiler, Georg
A1  - Phelan, Catherine M.
A1  - Piedmonte, Marion
A1  - Poppe, Bruce
A1  - Pujana, Miquel Angel
A1  - Radice, Paolo
A1  - Rennert, Gad
A1  - Rodriguez, Gustavo C.
A1  - Rookus, Matti A.
A1  - Ross, Eric A.
A1  - Schmutzler, Rita Katharina
A1  - Simard, Jacques
A1  - Singer, Christian F.
A1  - Slavin, Thomas P.
A1  - Soucy, Penny
A1  - Southey, Melissa
A1  - Steinemann, Doris
A1  - Stoppa-Lyonnet, Dominique
A1  - Sukiennicki, Grzegorz
A1  - Sutter, Christian
A1  - Szabo, Csilla I.
A1  - Tea, Muy-Kheng
A1  - Teixeira, Manuel R.
A1  - Teo, Soo-Hwang
A1  - Terry, Mary Beth
A1  - Thomassen, Mads
A1  - Tibiletti, Maria Grazia
A1  - Tihomirova, Laima
A1  - Tognazzo, Silvia
A1  - van Rensburg, Elizabeth J.
A1  - Varesco, Liliana
A1  - Varon-Mateeva, Raymonda
A1  - Vratimos, Athanassios
A1  - Weitzel, Jeffrey N.
A1  - McGuffog, Lesley
A1  - Kirk, Judy
A1  - Toland, Amanda Ewart
A1  - Hamann, Ute
A1  - Lindor, Noralane
A1  - Ramus, Susan J.
A1  - Greene, Mark H.
A1  - Couch, Fergus J.
A1  - Offit, Kenneth
A1  - Pharoah, Paul D. P.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
JF  - PLoS ONE
N2  - Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
KW  - fine-scale mapping
KW  - ovarian cancer
KW  - genetics
KW  - BRCA1
KW  - BRCA2
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166869
VL  - 11
IS  - 7
ER  - 
TY  - JOUR
A1  - Couch, Fergus J.
A1  - Wang, Xianshu
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Olswold, Curtis
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Fredericksen, Zachary
A1  - Barrowdale, Daniel
A1  - Dennis, Joe
A1  - Gaudet, Mia M.
A1  - Dicks, Ed
A1  - Kosel, Matthew
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Lee, Adam
A1  - Bacot, Françios
A1  - Vincent, Daniel
A1  - Hogervorst, Frans B. L.
A1  - Peock, Susan
A1  - Stoppa-Lyonnet, Dominique
A1  - Jakubowska, Anna
A1  - Radice, Paolo
A1  - Schmutzler, Rita Katharina
A1  - Domchek, Susan M.
A1  - Piedmonte, Marion
A1  - Singer, Christian F.
A1  - Friedman, Eitan
A1  - Thomassen, Mads
A1  - Hansen, Thomas V. O.
A1  - Neuhausen, Susan L.
A1  - Szabo, Csilla I.
A1  - Blanco, Ingnacio
A1  - Greene, Mark H.
A1  - Karlan, Beth Y.
A1  - Garber, Judy
A1  - Phelan, Catherine M.
A1  - Weitzel, Jeffrey N.
A1  - Montagna, Marco
A1  - Olah, Edith
A1  - Andrulis, Irene L.
A1  - Godwin, Andrew K.
A1  - Yannoukakos, Drakoulis
A1  - Goldgar, David E.
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Osorio, Ana
A1  - Terry, Mary Beth
A1  - Daly, Mary B.
A1  - van Rensburg, Elisabeth J.
A1  - Hamann, Ute
A1  - Ramus, Susan J.
A1  - Toland, Amanda Ewart
A1  - Caligo, Maria A.
A1  - Olopade, Olufunmilayo I.
A1  - Tung, Nadine
A1  - Claes, Kathleen
A1  - Beattie, Mary S.
A1  - Southey, Melissa C.
A1  - Imyanitov, Evgeny N.
A1  - Tischkowitz, Marc
A1  - Janavicius, Ramunas
A1  - John, Esther M.
A1  - Kwong, Ava
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Balmaña, Judith
A1  - Barkardottir, Rosa B.
A1  - Arun, Banu K.
A1  - Rennert, Gad
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Campbell, Ian
A1  - van der Hout, Annemarie H.
A1  - van Deurzen, Carolien H. M.
A1  - Seynaeve, Caroline
A1  - Garcia, Encarna B. Gómez
A1  - van Leeuwen, Flora E.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Gille, Johannes J. P.
A1  - Ausems, Magreet G. E. M.
A1  - Blok, Marinus J.
A1  - Ligtenberg, Marjolinjin J. L.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - Verhoef, Senno
A1  - van Os, Theo A. M.
A1  - Wijnen, Juul T.
A1  - Frost, Debra
A1  - Ellis, Steve
A1  - Fineberg, Elena
A1  - Platte, Radke
A1  - Evans, D. Gareth
A1  - Izatt, Luise
A1  - Eeles, Rosalind A.
A1  - Adlard, Julian
A1  - Eccles, Diana M.
A1  - Cook, Jackie
A1  - Brewer, Carole
A1  - Douglas, Fiona
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Side, Lucy E.
A1  - Donaldson, Alan
A1  - Houghton, Catherine
A1  - Rogers, Mark T.
A1  - Dorkins, Huw
A1  - Eason, Jacqueline
A1  - Gregory, Helen
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Calender, Alain
A1  - Hardouin, Agnès
A1  - Berthet, Pascaline
A1  - Delnatte, Capucine
A1  - Nogues, Catherine
A1  - Lasset, Christine
A1  - Houdayer, Claude
A1  - Leroux,, Dominique
A1  - Rouleau, Etienne
A1  - Prieur, Fabienne
A1  - Damiola, Francesca
A1  - Sobol, Hagay
A1  - Coupier, Isabelle
A1  - Venat-Bouvet, Laurence
A1  - Castera, Laurent
A1  - Gauthier-Villars, Marion
A1  - Léoné, Mélanie
A1  - Pujol, Pascal
A1  - Mazoyer, Sylvie
A1  - Bignon, Yves-Jean
A1  - Zlowocka-Perlowska, Elzbieta
A1  - Gronwald, Jacek
A1  - Lubinski,, Jan
A1  - Durda, Katarzyna
A1  - Jaworska, Katarzyna
A1  - Huzarski, Tomasz
A1  - Spurdle, Amanda B.
A1  - Viel, Alessandra
A1  - Peissel, Bernhard
A1  - Bonanni, Bernardo
A1  - Melloni, Guilia
A1  - Ottini, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Tibiletti, Maria Grazia
A1  - Peterlongo, Paolo
A1  - Volorio, Sara
A1  - Manoukian, Siranoush
A1  - Pensotti, Valeria
A1  - Arnold, Norbert
A1  - Engel, Christoph
A1  - Deissler, Helmut
A1  - Gadzicki, Dorothea
A1  - Gehrig, Andrea
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Ditsch, Nina
A1  - Plendl, Hansjoerg
A1  - Preisler-Adams, Sabine
A1  - Engert, Stefanie
A1  - Sutter, Christian
A1  - Varon-Mateeva, Raymenda
A1  - Wappenschmidt, Barbara
A1  - Weber, Bernhard H. F.
A1  - Arver, Brita
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Einbeigi, Zakaria
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Blank, Stephanie V.
A1  - Cohn, David E.
A1  - Rodriguez, Gustavo C.
A1  - Small, Laurie
A1  - Friedlander, Michael
A1  - Bae-Jump, Victoria L.
A1  - Fink-Retter, Anneliese
A1  - Rappaport, Christine
A1  - Gschwantler-Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Lindor, Noralane M.
A1  - Kaufman, Bella
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Skytte, Anne-Bine
A1  - Gerdes, Anne-Marie
A1  - Pedersen, Inge Sokilde
A1  - Moeller, Sanne Traasdahl
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Vijai, Joseph
A1  - Sarrel, Kara
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Ozcelik, Hilmi
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Jønson, Lars
A1  - Andersen, Mette K.
A1  - Ding, Yuan Chun
A1  - Steele, Linda
A1  - Foretova, Lenka
A1  - Teulé, Alex
A1  - Lazaro, Conxi
A1  - Brunet, Joan
A1  - Pujana, Miquel Angel
A1  - Mai, Phuong L.
A1  - Loud, Jennifer T.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Narod, Steven A.
A1  - Herzog, Josef
A1  - Sand, Sharon R.
A1  - Tognazzo, Silvia
A1  - Agata, Simona
A1  - Vaszko, Tibor
A1  - Weaver, Joellen
A1  - Stravropoulou, Alexandra V.
A1  - Buys, Saundra S.
A1  - Romero, Atocha
A1  - de la Hoya, Miguel
A1  - Aittomäki, Kristiina
A1  - Muranen, Taru A.
A1  - Duran, Mercedes
A1  - Chung, Wendy K.
A1  - Lasa, Adriana
A1  - Dorfling, Cecilia M.
A1  - Miron, Alexander
A1  - Benitez, Javier
A1  - Senter, Leigha
A1  - Huo, Dezheng
A1  - Chan, Salina B.
A1  - Sokolenko, Anna P.
A1  - Chiquette, Jocelyne
A1  - Tihomirova, Laima
A1  - Friebel, Tara M.
A1  - Agnarsson, Bjarne A.
A1  - Lu, Karen H.
A1  - Lejbkowicz, Flavio
A1  - James, Paul A.
A1  - Hall, Per
A1  - Dunning, Alison M.
A1  - Tessier, Daniel
A1  - Cunningham, Julie
A1  - Slager, Susan L.
A1  - Chen, Wang
A1  - Hart, Steven
A1  - Stevens, Kristen
A1  - Simard, Jacques
A1  - Pastinen, Tomi
A1  - Pankratz, Vernon S.
A1  - Offit, Kenneth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
JF  - PLOS Genetics
N2  - 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.
KW  - common variants
KW  - susceptibility alleles
KW  - genetic variants
KW  - modifiers
KW  - ZNF365
KW  - investigators
KW  - population
KW  - consortium
KW  - selection
KW  - subtypes
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947
SN  - 1553-7404
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Osorio, Ana
A1  - Milne, Roger L.
A1  - Kuchenbaecker, Karoline
A1  - Vaclová, Tereza
A1  - Pita, Guillermo
A1  - Alonso, Rosario
A1  - Peterlongo, Paolo
A1  - Blanco, Ignacio
A1  - de la Hoya, Miguel
A1  - Duran, Mercedes
A1  - Diez, Orland
A1  - Ramón y Cajal, Teresa
A1  - Konstantopoulou, Irene
A1  - Martínez-Bouzas, Christina
A1  - Conejero, Raquel Andrés
A1  - Soucy, Penny
A1  - McGuffog, Lesley
A1  - Barrowdale, Daniel
A1  - Lee, Andrew
A1  - Arver, Brita
A1  - Rantala, Johanna
A1  - Loman, Niklas
A1  - Ehrencrona, Hans
A1  - Olopade, Olufunmilayo I.
A1  - Beattie, Mary S.
A1  - Domchek, Susan M.
A1  - Nathanson, Katherine
A1  - Rebbeck, Timothy R.
A1  - Arun, Banu K.
A1  - Karlan, Beth Y.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - John, Esther M.
A1  - Whittemore, Alice S.
A1  - Daly, Mary B.
A1  - Southey, Melissa
A1  - Hopper, John
A1  - Terry, Mary B.
A1  - Buys, Saundra S.
A1  - Janavicius, Ramunas
A1  - Dorfling, Cecilia M.
A1  - van Rensburg, Elizabeth J.
A1  - Steele, Linda
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan Chun
A1  - Hansen, Thomas V. O.
A1  - Jønson, Lars
A1  - Ejlertsen, Bent
A1  - Gerdes, Anne-Marie
A1  - Infante, Mar
A1  - Herráez, Belén
A1  - Moreno, Leticia Thais
A1  - Weitzel, Jeffrey N.
A1  - Herzog, Josef
A1  - Weeman, Kisa
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Scuvera, Guilietta
A1  - Bonanni, Bernardo
A1  - Mariette, Frederique
A1  - Volorio, Sara
A1  - Viel, Alessandra
A1  - Varesco, Liliana
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Tibiletti, Maria Grazia
A1  - Radice, Paolo
A1  - Yannoukakos, Drakoulis
A1  - Garber, Judy
A1  - Ellis, Steve
A1  - Frost, Debra
A1  - Platte, Radka
A1  - Fineberg, Elena
A1  - Evans, Gareth
A1  - Lalloo, Fiona
A1  - Izatt, Louise
A1  - Eeles, Ros
A1  - Adlard, Julian
A1  - Davidson, Rosemarie
A1  - Cole, Trevor
A1  - Eccles, Diana
A1  - Cook, Jackie
A1  - Hodgson, Shirley
A1  - Brewer, Carole
A1  - Tischkowitz, Marc
A1  - Douglas, Fiona
A1  - Porteous, Mary
A1  - Side, Lucy
A1  - Walker, Lisa
A1  - Morrison, Patrick
A1  - Donaldson, Alan
A1  - Kennedy, John
A1  - Foo, Claire
A1  - Godwin, Andrew K.
A1  - Schmutzler, Rita Katharina
A1  - Wappenschmidt, Barbara
A1  - Rhiem, Kerstin
A1  - Engel, Christoph
A1  - Meindl, Alftons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Plendl, Hans Jörg
A1  - Niederacher, Dieter
A1  - Sutter, Christian
A1  - Wang-Gohrke, Shan
A1  - Steinemann, Doris
A1  - Preisler-Adams, Sabine
A1  - Kast, Karin
A1  - Varon-Mateeva, Raymonda
A1  - Gehrig, Andrea
A1  - Stoppa-Lyonnet, Dominique
A1  - Sinilnikova, Olga M.
A1  - Mazoyer, Sylvie
A1  - Damiola, Francesca
A1  - Poppe, Bruce
A1  - Claes, Kathleen
A1  - Piedmonte, Marion
A1  - Tucker, Kathy
A1  - Backes, Floor
A1  - Rodríguez, Gustavo
A1  - Brewster, Wendy
A1  - Wakeley, Katie
A1  - Rutherford, Thomas
A1  - Caldés, Trinidad
A1  - Nevanlinna, Heli
A1  - Aittomäki, Kristiina
A1  - Rookus, Matti A.
A1  - van Os, Theo A. M.
A1  - van der Kolk, Lizet
A1  - de Lange, J. L.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - van der Hout, A. H.
A1  - van Asperen, Christi J.
A1  - Goméz Garcia, Encarna B.
A1  - Encarna, B.
A1  - Hoogerbrugge, Nicoline
A1  - Collée, J. Margriet
A1  - van Deurzen, Carolien H. M.
A1  - van der Luijt, Rob B.
A1  - Devilee, Peter
A1  - Olah, Edith
A1  - Lázaro, Conxi
A1  - Teulé, Alex
A1  - Menéndez, Mireia
A1  - Jakubowska, Anna
A1  - Cybulski, Cezary
A1  - Gronwald, Jecek
A1  - Lubinski, Jan
A1  - Durda, Katarzyna
A1  - Jaworska-Bieniek, Katarzyna
A1  - Johannsson, Oskar Th.
A1  - Maugard, Christine
A1  - Montagna, Marco
A1  - Tognazzo, Silvia
A1  - Teixeira, Manuel R.
A1  - Healey, Sue
A1  - Olswold, Curtis
A1  - Guidugli, Lucia
A1  - Lindor, Noralane
A1  - Slager, Susan
A1  - Szabo, Csilla I.
A1  - Vijai, Joseph
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Zhang, Liying
A1  - Rau-Murthy, Rohini
A1  - Fink-Retter, Anneliese
A1  - Singer, Christine F.
A1  - Rappaport, Christine
A1  - Kaulich, Daphne Geschwantler
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Berger, Andreas
A1  - Phelan, Catherine M.
A1  - Greene, Mark H.
A1  - Mai, Phuong L.
A1  - Lejbkowicz, Flavio
A1  - Andrulis, Irene
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Toland, Amanda Ewart
A1  - Bojesen, Anders
A1  - Pedersen, Inge Sokilde
A1  - Sunde, Lone
A1  - Thomassen, Mads
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Friedman, Eitan
A1  - Laitman, Yeal
A1  - Shimon, Shanie Paluch
A1  - Simard, Jaques
A1  - Easton, Douglas F.
A1  - Offit, Kenneth
A1  - Couch, Fergus J.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
A1  - Benitez, Javier
T1  - DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
JF  - PLOS Genetics
N2  - Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
KW  - single-nucleotide polymorphisms
KW  - breast cancer
KW  - ovarian cancer
KW  - genetic modifiers
KW  - common variants
KW  - NEIL2
KW  - OGG1
KW  - investigators
KW  - consortium
KW  - damage
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116820
SN  - 1553-7404
VL  - 4
IS  - e1004256
ER  - 
TY  - THES
A1  - Jensen, Katharina
T1  - Untersuchungen zum mRNA Trans-Spleißen bei den humanparasitischen Cestoden Echinococcus multilocularis und Echinococcus granulosus
T1  - mRNA trans-splicing in the human parasitic cestode Echinococcus multilocularis and Echinococcus granulosus
N2  - SL-Trans-Spleißen ist ein Mechanismus zur Transkriptprozessierung, welcher bisher bei kinetoplastiden Protozoen, Trematoden und Nematoden beschrieben wurde. Im Rahmen der vorliegenden Arbeit wurde erstmals das Gen für einen Spliced Leader (SL) aus den Cestoden E. multilocularis und E. granulosus charakterisiert. Ausgangspunkt waren Studien zur Genregulation des E. multilocularis Gens elp, welches für einen Faktor der ERM-Familie kodiert. Es konnte gezeigt werden, daß elp über mindestens zwei unterschiedliche Transkripte kodiert wird. Für eines dieser Transkripte konnte gezeigt werden, daß ein 32 Nukleotide langes, nicht-proteinkodierendes Exon über konservatives Spleißen mit dem startmethionin-kodierenden Exon II der elp-mRNA fusioniert wird. Der entsprechende Transkriptionsstartpunkt und zugehörige Promotorstrukturen konnten auf dem E. multilocularis Chromosom identifiziert werden. Ein zweites Transkript enthielt anstelle des 32 nt Exon I von elp ein alternatives 36 nt langes Exon am 5‘-Ende, welches nicht Teil des genomischen elp Lokus ist. Im Rahmen der vorliegenden Arbeit wurde gezeigt, daß dieses 36 nt lange Exon einen Spliced Leader (SL) von E. multilocularis darstellt. Eine Analyse von E. multilocularis cDNA-Bibliotheken ergab, daß sich das 36 nt Exon nicht nur am 5‘-Ende der elp-mRNA befindet, sondern in identischer Form auch am 5‘-Ende von mindestens elf anderen mRNAs von E. multilocularis. Das zugehörige SL-RNA-Gen konnte isoliert und vollständig charakterisiert werden. Es befand sich auf einem 1513 bp langen Fragment, welches auf dem E. multilocularis Genom als mehrfacher Repeat angeordnet ist. Auf DNA-Sequenzebene konnte gezeigt werden, daß dieses Gen signifikante Homologien zu bereits bekannten SL-RNA-Sequenzen von Trematoden und Turbellaria nicht jedoch zu solchen von Nematoden und kinetoplastiden Protozoen aufweist. Die Sekundärstruktur der kodierten SL-RNA besitzt zudem strukturelle Charakteristika, die für SL-RNAs anderer Organismen bereits bekannt sind. Zusammengenommen lassen diese Daten den Schluß zu, daß es sich bei dem 36 nt langen Exon in der Tat um einen SL von E. multilocularis handelt. Die für E. multilocularis identifizierten trans-gespleißten mRNAs kodieren für Faktoren, welche an einer Reihe unterschiedlicher Prozesse in der Zelle beteiligt sind. Signifikante Unterschiede in den Spektren der trans-gespleißten Faktoren bei Echinococcus und anderen Plathelminthen können als Hinweis gewertet werden, daß keine generelle Korrelation besteht zwischen Trans-Spleißen einer bestimmten mRNA und der biologischen Funktion des Faktors. Ein zum SL-Gen von E. multilocularis hoch homologes Gen konnte zudem auf chromosomaler DNA des Hundebandwurms E. granulosus identifiziert werden. Trans-Spleißen wird demnach nicht nur vom Fuchsbandwurm, sondern auch vom Hundebandwurm zur Genexpression genutzt. Im Falle von elp besteht die ungewöhnliche Situation, daß ein identisches Protein zwei verschiedene Transkripte kodiert von denen eines konventionell und das andere trans-gespleißt wird. Der Regulationsmechanismus dieses alternativen Cis/Trans-Spleißens wurde in dieser Arbeit untersucht. Hierbei konnte gezeigt werden, daß den zwei elp Transkripten auch zwei unterschiedliche Primärtranskripte zugrunde liegen. Die dabei erlangten Daten stehen in Einklang mit dem gegenwärtigen Modell, daß alternatives Cis/Trans-Spleißen an einer Splice Akzeptorstelle ausschließlich vom Vorhandensein einer stromaufwärts gelegenen Splice Donorstelle abhängt. Weitere Studien haben gezeigt, daß die Expression der trans-oder cis-gespleißten elp-mRNA weder stadien- noch isolat-oder zytospezifische ist. Zusammenfassend konnten in dieser Arbeit erstmals umfassende Daten zum Mechanismus des Trans-Spleißens bei einem Cestoden erlangt werden, was sich für weitere molekularbiologische Untersuchungen an diesem Organismus hervorragend ausnutzen läßt. In einer abschließenden Studie wurde versucht einen weiteren ERM-homologen Faktor, der eventuell auch über alternatives Cis/Trans-Spleißen exprimiert wird, über PCR mit degenerativen Primern zu identifizieren. Es konnte jedoch neben elp kein anderer homologer Faktor bestimmt werden. Dieses Ergebnis entspricht den bereits bei anderen niederen Eukaryonten durchgeführten Untersuchungen.
N2  - For information in english regarding this dissertation please have a look at the following references: Brehm K, Jensen K, Frosch M (1999) Characterization of the genomic locus expressing the ERM-like protein of Echinococcus multilocularis. Mol Biochem Parasitol. 15, 147-152 Brehm K, Jensen K, Frosch M (2000) mRNA trans-splicing in the human parasitic cestode Echinococcus multilocularis. J Biol Chem. 275, 38311-38318
KW  - Trans-Spleißen
KW  - Spleißen
KW  - Cestoden
KW  - Echinococcus
KW  - mRNA
KW  - splicing
KW  - echinococcus
KW  - cestode
KW  - trans-splicing
KW  - mRNA
Y1  - 2002
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5842
ER  -