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Hansmann, Tamara ; Pliushch, Galyna ; Leubner, Monika ; Kroll, Patricia ; Endt, Daniela ; Gehrig, Andrea ; Preisler-Adams, Sabine ; Wieacker, Peter ; Haaf, Thomas
Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4%) patients with constitutive BRCA1 and three (0.5%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12–40%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.
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.
Osorio, Ana ; Milne, Roger L. ; Kuchenbaecker, Karoline ; Vaclová, Tereza ; Pita, Guillermo ; Alonso, Rosario ; Peterlongo, Paolo ; Blanco, Ignacio ; de la Hoya, Miguel ; Duran, Mercedes ; Diez, Orland ; Ramón y Cajal, Teresa ; Konstantopoulou, Irene ; Martínez-Bouzas, Christina ; Conejero, Raquel Andrés ; Soucy, Penny ; McGuffog, Lesley ; Barrowdale, Daniel ; Lee, Andrew ; Arver, Brita ; Rantala, Johanna ; Loman, Niklas ; Ehrencrona, Hans ; Olopade, Olufunmilayo I. ; Beattie, Mary S. ; Domchek, Susan M. ; Nathanson, Katherine ; Rebbeck, Timothy R. ; Arun, Banu K. ; Karlan, Beth Y. ; Walsh, Christine ; Lester, Jenny ; John, Esther M. ; Whittemore, Alice S. ; Daly, Mary B. ; Southey, Melissa ; Hopper, John ; Terry, Mary B. ; Buys, Saundra S. ; Janavicius, Ramunas ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Steele, Linda ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Hansen, Thomas V. O. ; Jønson, Lars ; Ejlertsen, Bent ; Gerdes, Anne-Marie ; Infante, Mar ; Herráez, Belén ; Moreno, Leticia Thais ; Weitzel, Jeffrey N. ; Herzog, Josef ; Weeman, Kisa ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Guilietta ; Bonanni, Bernardo ; Mariette, Frederique ; Volorio, Sara ; Viel, Alessandra ; Varesco, Liliana ; Papi, Laura ; Ottini, Laura ; Tibiletti, Maria Grazia ; Radice, Paolo ; Yannoukakos, Drakoulis ; Garber, Judy ; Ellis, Steve ; Frost, Debra ; Platte, Radka ; Fineberg, Elena ; Evans, Gareth ; Lalloo, Fiona ; Izatt, Louise ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Eccles, Diana ; Cook, Jackie ; Hodgson, Shirley ; Brewer, Carole ; Tischkowitz, Marc ; Douglas, Fiona ; Porteous, Mary ; Side, Lucy ; Walker, Lisa ; Morrison, Patrick ; Donaldson, Alan ; Kennedy, John ; Foo, Claire ; Godwin, Andrew K. ; Schmutzler, Rita Katharina ; Wappenschmidt, Barbara ; Rhiem, Kerstin ; Engel, Christoph ; Meindl, Alftons ; Ditsch, Nina ; Arnold, Norbert ; Plendl, Hans Jörg ; Niederacher, Dieter ; Sutter, Christian ; Wang-Gohrke, Shan ; Steinemann, Doris ; Preisler-Adams, Sabine ; Kast, Karin ; Varon-Mateeva, Raymonda ; Gehrig, Andrea ; Stoppa-Lyonnet, Dominique ; Sinilnikova, Olga M. ; Mazoyer, Sylvie ; Damiola, Francesca ; Poppe, Bruce ; Claes, Kathleen ; Piedmonte, Marion ; Tucker, Kathy ; Backes, Floor ; Rodríguez, Gustavo ; Brewster, Wendy ; Wakeley, Katie ; Rutherford, Thomas ; Caldés, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Rookus, Matti A. ; van Os, Theo A. M. ; van der Kolk, Lizet ; de Lange, J. L. ; Meijers-Heijboer, Hanne E. J. ; van der Hout, A. H. ; van Asperen, Christi J. ; Goméz Garcia, Encarna B. ; Encarna, B. ; Hoogerbrugge, Nicoline ; Collée, J. Margriet ; van Deurzen, Carolien H. M. ; van der Luijt, Rob B. ; Devilee, Peter ; Olah, Edith ; Lázaro, Conxi ; Teulé, Alex ; Menéndez, Mireia ; Jakubowska, Anna ; Cybulski, Cezary ; Gronwald, Jecek ; Lubinski, Jan ; Durda, Katarzyna ; Jaworska-Bieniek, Katarzyna ; Johannsson, Oskar Th. ; Maugard, Christine ; Montagna, Marco ; Tognazzo, Silvia ; Teixeira, Manuel R. ; Healey, Sue ; Olswold, Curtis ; Guidugli, Lucia ; Lindor, Noralane ; Slager, Susan ; Szabo, Csilla I. ; Vijai, Joseph ; Robson, Mark ; Kauff, Noah ; Zhang, Liying ; Rau-Murthy, Rohini ; Fink-Retter, Anneliese ; Singer, Christine F. ; Rappaport, Christine ; Kaulich, Daphne Geschwantler ; Pfeiler, Georg ; Tea, Muy-Kheng ; Berger, Andreas ; Phelan, Catherine M. ; Greene, Mark H. ; Mai, Phuong L. ; Lejbkowicz, Flavio ; Andrulis, Irene ; Mulligan, Anna Marie ; Glendon, Gord ; Toland, Amanda Ewart ; Bojesen, Anders ; Pedersen, Inge Sokilde ; Sunde, Lone ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Friedman, Eitan ; Laitman, Yeal ; Shimon, Shanie Paluch ; Simard, Jaques ; Easton, Douglas F. ; Offit, Kenneth ; Couch, Fergus J. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Benitez, Javier
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.