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Identification of six new susceptibility loci for invasive epithelial ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation … carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P \textless 5 \times 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Authors: Karoline B. Kuchenbaecker, Susan J. Ramus, Jonathan Tyrer, Andrew Lee, Howard C. Shen, Jonathan Beesley, Kate Lawrenson, Lesley McGuffog, Sue Healey, Janet M. Lee, Tassja J. Spindler, Yvonne G. Lin, Tanja Pejovic, Yukie Bean, Qiyuan Li, Simon Coetzee, Dennis Hazelett, Alexander Miron, Melissa Southey, Mary Beth Terry, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Susan L. Neuhausen, Yuan Chun Ding, Thomas v. O. Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Daniel Barrowdale, Joe Dennis, Javier Benitez, Ana Osorio, Maria Jose Garcia, Ian Komenaka, Jeffrey N. Weitzel, Pamela Ganschow, Paolo Peterlongo, Loris Bernard, Alessandra Viel, Bernardo Bonanni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Laura Papi, Laura Ottini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Debra Frost, Jo Perkins, Radka Platte, Steve Ellis, Andrew K. Godwin, Rita Katharina Schmutzler, Alfons Meindl, Christoph Engel, Christian Sutter, Olga M. Sinilnikova, Francesca Damiola, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Kathleen Claes, Kim de Leeneer, Judy Kirk, Gustavo C. Rodriguez, Marion Piedmonte, David M. O’Malley, Miguel de La Hoya, Trinidad Caldes, Kristiina Aittomäki, Heli Nevanlinna, J. Margriet Collée, Matti A. Rookus, Jan C. Oosterwijk, Laima Tihomirova, Nadine Tung, Ute Hamann, Claudine Isaccs, Marc Tischkowitz, Evgeny N. Imyanitov, Maria A. Caligo, Ian G. Campbell, Frans B. L. Hogervorst, Edith Olah, Orland Diez, Ignacio Blanco, Joan Brunet, Conxi Lazaro, Miquel Angel Pujana, Anna Jakubowska, Jacek Gronwald, Jan Lubinski, Grzegorz Sukiennicki, Rosa B. Barkardottir, Marie Plante, Jacques Simard, Penny Soucy, Marco Montagna, Silvia Tognazzo, Manuel R. Teixeira, Vernon S. Pankratz, Xianshu Wang, Noralane Lindor, Csilla I. Szabo, Noah Kauff, Joseph Vijai, Carol A. Aghajanian, Georg Pfeiler, Andreas Berger, Christian F. Singer, Muy-Kheng Tea, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Gad Rennert, Anna Marie Mulligan, Sandrine Tchatchou, Irene L. Andrulis, Gord Glendon, Amanda Ewart Toland, Uffe Birk Jensen, Torben A. Kruse, Mads Thomassen, Anders Bojesen, Jamal Zidan, Eitan Friedman, Yael Laitman, Maria Soller, Annelie Liljegren, Brita Arver, Zakaria Einbeigi, Marie Stenmark-Askmalm, Olufunmilayo I. Olopade, Robert L. Nussbaum, Timothy R. Rebbeck, Katherine L. Nathanson, Susan M. Domchek, Karen H. Lu, Beth Y. Karlan, Christine Walsh, Jenny Lester, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Diether Lambrechts, Els van Nieuwenhuysen, Ignace Vergote, Sandrina Lambrechts, Ed Dicks, Jennifer A. Doherty, Kristine G. Wicklund, Mary Anne Rossing, Anja Rudolph, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Kirsten B. Moysich, Kunle Odunsi, Lara Sucheston, Shashi Lele, Lynne R. Wilkens, Marc T. Goodman, Pamela J. Thompson, Yurii B. Shvetsov, Ingo B. Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Liisa M. Pelttari, Ralf Butzow, Francesmary Modugno, Joseph L. Kelley, Robert P. Edwards, Roberta B. Ness, Andreas Du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Keitaro Matsuo, Satoyo Hosono, Sandra Orsulic, Allan Jensen, Susanne Kruger Kjaer, Estrid Hogdall, Hanis Nazihah Hasmad, Mat Adenan Noor Azmi, Soo-Hwang Teo, Yin-Ling Woo, Brooke L. Fridley, Ellen L. Goode, Julie M. Cunningham, Robert A. Vierkant, Fiona Bruinsma, Graham G. Giles, Dong Liang, Michelle A. T. Hildebrandt, Xifeng Wu, Douglas A. Levine, Maria Bisogna, Andrew Berchuck, Edwin S. Iversen, Joellen M. Schildkraut, Patrick Concannon, Rachel Palmieri Weber, Daniel W. Cramer, Kathryn L. Terry, Elizabeth M. Poole, Shelley S. Tworoger, Elisa V. Bandera, Irene Orlow, Sara H. Olson, Camilla Krakstad, Helga B. Salvesen, Ingvild L. Tangen, Line Bjorge, Anne M. van Altena, Katja K. H. Aben, Lambertus A. Kiemeney, Leon F. A. G. Massuger, Melissa Kellar, Angela Brooks-Wilson, Linda E. Kelemen, Linda S. Cook, Nhu D. Le, Cezary Cybulski, Hannah Yang, Jolanta Lissowska, Louise A. Brinton, Nicolas Wentzensen, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Helen Baker, Honglin Song, Diana Eccles, Ian McNeish, James Paul, Karen Carty, Nadeem Siddiqui, Rosalind Glasspool, Alice S. Whittemore, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Bu-Tian Ji, Wei Zheng, Xiao-Ou Shu, Yu-Tang Gao, Barry Rosen, Harvey A. Risch, John R. McLaughlin, Steven A. Narod, Alvaro N. Monteiro, Ann Chen, Hui-Yi Lin, Jenny Permuth-Wey, Thomas A. Sellers, Ya-Yu Tsai, Zhihua Chen, Argyrios Ziogas, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Usha Menon, Patricia Harrington, Alice W. Lee, Anna H. Wu, Celeste L. Pearce, Gerry Coetzee, Malcolm C. Pike, Agnieszka Dansonka-Mieszkowska, Agnieszka Timorek, Iwona K. Rzepecka, Jolanta Kupryjanczyk, Matt Freedman, Houtan Noushmehr, Douglas F. Easton, Kenneth Offit, Fergus J. Couch, Simon Gayther, Paul P. Pharoah, Antonis C. Antoniou, Georgia Chenevix-Trench

Date Published: 1st Feb 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers …s of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Authors: Paolo Peterlongo, Jenny Chang-Claude, Kirsten B. Moysich, Anja Rudolph, Rita K. Schmutzler, Jacques Simard, Penny Soucy, Rosalind A. Eeles, Douglas F. Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A. Rookus, Marjanka K. Schmidt, Frederieke H. van der Baan, Amanda B. Spurdle, Logan C. Walker, Felicity Lose, Ana-Teresa Maia, Marco Montagna, Laura Matricardi, Jan Lubinski, Anna Jakubowska, Encarna B. Gómez Garcia, Olufunmilayo I. Olopade, Robert L. Nussbaum, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Sandra Orsulic, Jenny Lester, Wendy K. Chung, Alex Miron, Melissa C. Southey, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Yuan Chun Ding, Susan L. Neuhausen, Thomas v. O. Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Lars Jønson, Ana Osorio, Cristina Martínez-Bouzas, Javier Benitez, Edye E. Conway, Kathleen R. Blazer, Jeffrey N. Weitzel, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Monica Barile, Filomena Ficarazzi, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Giuseppe Giannini, Laura Papi, Aline Martayan, Maria Grazia Tibiletti, Paolo Radice, Athanassios Vratimos, Florentia Fostira, Judy E. Garber, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth R. Evans, Debra Frost, Diana Eccles, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Rosemarie Davidson, Shirley V. Hodgson, Steve Ellis, Trevor Cole, Andrew K. Godwin, Kathleen Claes, Tom van Maerken, Alfons Meindl, Andrea Gehrig, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Shan Wang-Gohrke, Brigitte Bressac-de Paillerets, Bruno Buecher, Capucine Delnatte, Claude Houdayer, Dominique Stoppa-Lyonnet, Francesca Damiola, Isabelle Coupier, Laure Barjhoux, Laurence Venat-Bouvet, Lisa Golmard, Nadia Boutry-Kryza, Olga M. Sinilnikova, Olivier Caron, Pascal Pujol, Sylvie Mazoyer, Muriel Belotti, Marion Piedmonte, Michael L. Friedlander, Gustavo C. Rodriguez, Larry J. Copeland, Miguel de La Hoya, Pedro Perez Segura, Heli Nevanlinna, Kristiina Aittomäki, Theo A. M. van Os, Hanne E. J. Meijers-Heijboer, Annemarie H. van der Hout, Maaike P. G. Vreeswijk, Nicoline Hoogerbrugge, Margreet G. E. M. Ausems, Helena C. van Doorn, J. Margriet Collée, Edith Olah, Orland Diez, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Lidia Feliubadalo, Cezary Cybulski, Jacek Gronwald, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Grzegorz Sukiennicki, Adalgeir Arason, Jocelyne Chiquette, Manuel R. Teixeira, Curtis Olswold, Fergus J. Couch, Noralane M. Lindor, Xianshu Wang, Csilla I. Szabo, Kenneth Offit, Marina Corines, Lauren Jacobs, Mark E. Robson, Liying Zhang, Vijai Joseph, Andreas Berger, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng M. Tea, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Gad Rennert, Anna Marie Mulligan, Gord Glendon, Sandrine Tchatchou, Irene L. Andrulis, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Mads Thomassen, Uffe Birk Jensen, Yael Laitman, Johanna Rantala, Anna von Wachenfeldt, Hans Ehrencrona, Marie Stenmark Askmalm, Åke Borg, Karoline B. Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Sue Healey, Andrew Lee, Paul D. P. Pharoah, Georgia Chenevix-Trench, Antonis C. Antoniou, Eitan Friedman

Date Published: 13th Jan 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological …l features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Authors: Amanda B. Spurdle, Fergus J. Couch, Michael T. Parsons, Lesley McGuffog, Daniel Barrowdale, Manjeet K. Bolla, Qin Wang, Sue Healey, Rita Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Steve Ellis, Debra Frost, Radka Platte, Jo Perkins, D. Gareth Evans, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Giulietta Scuvera, Siranoush Manoukian, Bernardo Bonanni, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Barbara Pasini, Laura Papi, Liliana Varesco, Rosemary Balleine, Katherine L. Nathanson, Susan M. Domchek, Kenneth Offitt, Anna Jakubowska, Noralane Lindor, Mads Thomassen, Uffe Birk Jensen, Johanna Rantala, Åke Borg, Irene L. Andrulis, Alexander Miron, Thomas v. O. Hansen, Trinidad Caldes, Susan L. Neuhausen, Amanda E. Toland, Heli Nevanlinna, Marco Montagna, Judy Garber, Andrew K. Godwin, Ana Osorio, Rachel E. Factor, Mary B. Terry, Timothy R. Rebbeck, Beth Y. Karlan, Melissa Southey, Muhammad Usman Rashid, Nadine Tung, Paul D. P. Pharoah, Fiona M. Blows, Alison M. Dunning, Elena Provenzano, Per Hall, Kamila Czene, Marjanka K. Schmidt, Annegien Broeks, Sten Cornelissen, Senno Verhoef, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Dennis J. Slamon, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Petra Seibold, Kristiina Aittomäki, Taru A. Muranen, Päivi Heikkilä, Carl Blomqvist, Jonine Figueroa, Stephen J. Chanock, Louise Brinton, Jolanta Lissowska, Janet E. Olson, Vernon S. Pankratz, Esther M. John, Alice S. Whittemore, Dee W. West, Ute Hamann, Diana Torres, Hans Ulrich Ulmer, Thomas Rüdiger, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. van Asperen, Diana M. Eccles, William J. Tapper, Lorraine Durcan, Louise Jones, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Miriam Dwek, Ruth Swann, Anita L. Bane, Gord Glendon, Anna M. Mulligan, Graham G. Giles, Roger L. Milne, Laura Baglietto, Catriona McLean, Jane Carpenter, Christine Clarke, Rodney Scott, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Thilo Dörk, Natalia Bogdanova, Tjoung-Won Park-Simon, Peter Hillemanns, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Barbara Burwinkel, Frederik Marme, Harald Surovy, Rongxi Yang, Hoda Anton-Culver, Argyrios Ziogas, Maartje J. Hooning, J. Margriet Collée, John W. M. Martens, Madeleine M. A. Tilanus-Linthorst, Hermann Brenner, Aida Karina Dieffenbach, Volke Arndt, Christa Stegmaier, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Annika Lindblom, Sara Margolin, Vijai Joseph, Mark Robson, Rohini Rau-Murthy, Anna González-Neira, José Ignacio Arias, Pilar Zamora, Javier Benítez, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Paolo Peterlongo, Daniela Zaffaroni, Monica Barile, Fabio Capra, Paolo Radice, Soo H. Teo, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix-Trench, David E. Goldgar

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. …. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P \textless10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Authors: Karoline B. Kuchenbaecker, Susan L. Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L. Andrulis, Amanda B. Spurdle, Marjanka K. Schmidt, Rita K. Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Andrew Lee, Sue Healey, Robert L. Nussbaum, Timothy R. Rebbeck, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester, Ilana Cass, Mary Beth Terry, Mary B. Daly, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Thomas v O Hansen, Bent Ejlertsen, Anne-Marie Gerdes, Finn C. Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Isaac Tafur, Mary Hander, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Gaia Roversi, Giulietta Scuvera, Bernardo Bonanni, Paolo Mariani, Sara Volorio, Riccardo Dolcetti, Liliana Varesco, Laura Papi, Maria Grazia Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai-Ren Ong, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew K. Godwin, Kerstin Rhiem, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Doris Steinemann, Nadja Bogdanova-Markov, Karin Kast, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Andrea Gehrig, Birgid Markiefka, Bruno Buecher, Cédrick Lefol, Dominique Stoppa-Lyonnet, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Laure Barjhoux, Laurence Faivre, Michel Longy, Nicolas Sevenet, Olga M. Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Claudine Isaacs, Tom van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo C. Rodriguez, Trinidad Caldes, Miguel de La Hoya, Sofia Khan, Frans B. L. Hogervorst, Cora M. Aalfs, J. L. de Lange, Hanne E. J. Meijers-Heijboer, Annemarie H. van der Hout, Juul T. Wijnen, K. E. P. van Roozendaal, Arjen R. Mensenkamp, Ans M. W. van den Ouweland, Carolien H. M. van Deurzen, Rob B. van der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, Ignacio Blanco, Alex Teulé, Mireia Menendez, Anna Jakubowska, Jan Lubinski, Cezary Cybulski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Adalgeir Arason, Christine Maugard, Penny Soucy, Marco Montagna, Simona Agata, Manuel R. Teixeira, Curtis Olswold, Noralane Lindor, Vernon S. Pankratz, Emily Hallberg, Xianshu Wang, Csilla I. Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Catherine M. Phelan, Phuong L. Mai, Mark H. Greene, Gad Rennert, Evgeny N. Imyanitov, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I. Olopade, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Antonis C. Antoniou

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

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\textless0.05 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 = 2.7 \times 10(-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 = 4.8 \times 10(-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.

Authors: Ana Osorio, Roger L. Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de La Hoya, Mercedes Duran, Orland Díez, Teresa Ramón y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Swe-Brca, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I. Olopade, Mary S. Beattie, Susan M. Domchek, Katherine Nathanson, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Christine Walsh, Jenny Lester, Esther M. John, Alice S. Whittemore, Mary B. Daly, Melissa Southey, John Hopper, Mary B. Terry, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Susan L. Neuhausen, Yuan Chun Ding, Thomas v. O. Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belén Herráez, Leticia Thais Moreno, Jeffrey N. Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K. Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodríguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A. Rookus, Theo A. M. van Os, Lizet van der Kolk, J. L. de Lange, Hanne E. J. Meijers-Heijboer, A. H. van der Hout, Christi J. van Asperen, Encarna B. Gómez Garcia, Nicoline Hoogerbrugge, J. Margriet Collée, Carolien H. M. van Deurzen, Rob B. van der Luijt, Peter Devilee, Hebon, Edith Olah, Conxi Lázaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R. Teixeira, Sue Healey, Kconfab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I. Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M. Phelan, Mark H. Greene, Phuong L. Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F. Easton, Kenneth Offit, Fergus J. Couch, Georgia Chenevix-Trench, Antonis C. Antoniou, Javier Benitez

Date Published: 3rd Apr 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in … case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER\textgreeka to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

Authors: Kerstin B. Meyer, Martin O’Reilly, Kyriaki Michailidou, Saskia Carlebur, Stacey L. Edwards, Juliet D. French, Radhika Prathalingham, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ines de Santiago, John L. Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Laura J. van ’t Veer, Frans B. Hogervorst, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Michael P. Lux, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, Jose I. Arias, Javier Benitez, Susan Neuhausen, Hoda Anton-Culver, Argyrios Ziogas, Christina C. Dur, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Rita K. Schmutzler, Christoph Engel, Nina Ditsch, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Thilo Dörk, Sonja Helbig, Natalia V. Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-Trench, Anna H. Wu, Chiu-Chen Tseng, David van den Berg, Daniel O. Stram, Diether Lambrechts, Bernard Thienpont, Marie-Rose Christiaens, Ann Smeets, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Loris Bernard, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Kristen Purrington, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo-Hwang Teo, Cheng-Har Yip, Sze-Yee Phuah, Vessela Kristensen, Grethe Grenaker Alnæs, Anne-Lise Børresen-Dale, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A. E. M. Tollenaar, Caroline M. Seynaeve, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Hartef Darabi, Kimael Eriksson, Maartje J. Hooning, John W. M. Martens, Ans M. W. van den Ouweland, Carolien H. M. van Deurzen, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Malcolm W. R. Reed, William Blot, Lisa B. Signorello, Qiuyin Cai, Paul D. P. Pharoah, Maya Ghoussaini, Patricia Harrington, Jonathan Tyrer, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Mikael Hartman, Miao Hui, Wei-Yen Lim, Shaik A. Buhari, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans-Ulrich Ulmer, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Celine Vachon, Susan Slager, Florentia Fostira, Robert Pilarski, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A. J. Ponder, Alison M. Dunning, Douglas F. Easton

Date Published: 1st Dec 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used … to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Authors: C. Fischer, K. Kuchenbacker, C. Engel, S. Zachariae, K. Rhiem, A. Meindl, N. Rahner, N. Dikow, H. Plendl, I. Debatin, T. Grimm, D. Gadzicki, R. Flottmann, J. Horvath, E. Schrock, F. Stock, D. Schafer, I. Schwaab, C. Kartsonaki, N. Mavaddat, B. Schlegelberger, A. C. Antoniou, R. Schmutzler

Date Published: 9th Apr 2013

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

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