Publications

96 Publications visible to you, out of a total of 96

Abstract (Expand)

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed \sim480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 \times 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 \times 10(-8)) and BRCA1 mutation carrier (P = 1.1 \times 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 \times 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 \times 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 \times 10(-12)) and BRCA1 mutation carrier (P = 1.6 \times 10(-14)) breast and invasive ovarian (P = 1.3 \times 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Authors: Stig E. Bojesen, Karen A. Pooley, Sharon E. Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P. Tyrer, Stacey L. Edwards, Hilda A. Pickett, Howard C. Shen, Chanel E. Smart, Kristine M. Hillman, Phuong L. Mai, Kate Lawrenson, Michael D. Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L. Johnston, Juliet D. French, Xiaoqing Chen, Maren Weischer, Sune F. Nielsen, Melanie J. Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K. Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Michael Lush, Daniel C. Tessier, Daniel Vincent, Françis Bacot, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A. Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A. Doherty, Nuria Alvarez, Melissa C. Larson, Brooke L. Fridley, Nils Schoof, Jenny Chang-Claude, Mine S. Cicek, Julian Peto, Kimberly R. Kalli, Annegien Broeks, Sebastian M. Armasu, Marjanka K. Schmidt, Linde M. Braaf, Boris Winterhoff, Heli Nevanlinna, Gottfried E. Konecny, Diether Lambrechts, Lisa Rogmann, Pascal Guénel, Attila Teoman, Roger L. Milne, Joaquin J. Garcia, Angela Cox, Vijayalakshmi Shridhar, Barbara Burwinkel, Frederik Marme, Rebecca Hein, Elinor J. Sawyer, Christopher A. Haiman, Shan Wang-Gohrke, Irene L. Andrulis, Kirsten B. Moysich, John L. Hopper, Kunle Odunsi, Annika Lindblom, Graham G. Giles, Hermann Brenner, Jacques Simard, Galina Lurie, Peter A. Fasching, Michael E. Carney, Paolo Radice, Lynne R. Wilkens, Anthony Swerdlow, Marc T. Goodman, Hiltrud Brauch, Montserrat Garcia-Closas, Peter Hillemanns, Robert Winqvist, Matthias Dürst, Peter Devilee, Ingo Runnebaum, Anna Jakubowska, Jan Lubinski, Arto Mannermaa, Ralf Butzow, Natalia V. Bogdanova, Thilo Dörk, Liisa M. Pelttari, Wei Zheng, Arto Leminen, Hoda Anton-Culver, Clareann H. Bunker, Vessela Kristensen, Roberta B. Ness, Kenneth Muir, Robert Edwards, Alfons Meindl, Florian Heitz, Keitaro Matsuo, Andreas Du Bois, Anna H. Wu, Philipp Harter, Soo-Hwang Teo, Ira Schwaab, Xiao-Ou Shu, William Blot, Satoyo Hosono, Daehee Kang, Toru Nakanishi, Mikael Hartman, Yasushi Yatabe, Ute Hamann, Beth Y. Karlan, Suleeporn Sangrajrang, Susanne Krüger Kjaer, Valerie Gaborieau, Allan Jensen, Diana Eccles, Estrid Høgdall, Chen-Yang Shen, Judith Brown, Yin Ling Woo, Mitul Shah, Mat Adenan Noor Azmi, Robert Luben, Siti Zawiah Omar, Kamila Czene, Robert A. Vierkant, Børge G. Nordestgaard, Henrik Flyger, Celine Vachon, Janet E. Olson, Xianshu Wang, Douglas A. Levine, Anja Rudolph, Rachel Palmieri Weber, Dieter Flesch-Janys, Edwin Iversen, Stefan Nickels, Joellen M. Schildkraut, Isabel Dos Santos Silva, Daniel W. Cramer, Lorna Gibson, Kathryn L. Terry, Olivia Fletcher, Allison F. Vitonis, C. Ellen van der Schoot, Elizabeth M. Poole, Frans B. L. Hogervorst, Shelley S. Tworoger, Jianjun Liu, Elisa V. Bandera, Jingmei Li, Sara H. Olson, Keith Humphreys, Irene Orlow, Carl Blomqvist, Lorna Rodriguez-Rodriguez, Kristiina Aittomäki, Helga B. Salvesen, Taru A. Muranen, Elisabeth Wik, Barbara Brouwers, Camilla Krakstad, Els Wauters, Mari K. Halle, Hans Wildiers, Lambertus A. Kiemeney, Claire Mulot, Katja K. Aben, Pierre Laurent-Puig, Anne Mvan Altena, Thérèse Truong, Leon F. A. G. Massuger, Javier Benitez, Tanja Pejovic, Jose Ignacio Arias Perez, Maureen Hoatlin, M. Pilar Zamora, Linda S. Cook, Sabapathy P. Balasubramanian, Linda E. Kelemen, Andreas Schneeweiss, Nhu D. Le, Christof Sohn, Angela Brooks-Wilson, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Cezary Cybulski, Brian E. Henderson, Janusz Menkiszak, Fredrick Schumacher, Nicolas Wentzensen, Loic Le Marchand, Hannah P. Yang, Anna Marie Mulligan, Gord Glendon, Svend Aage Engelholm, Julia A. Knight, Claus K. Høgdall, Carmel Apicella, Martin Gore, Helen Tsimiklis, Honglin Song, Melissa C. Southey, Agnes Jager, Ans M. Wvan den Ouweland, Robert Brown, John W. M. Martens, James M. Flanagan, Mieke Kriege, James Paul, Sara Margolin, Nadeem Siddiqui, Gianluca Severi, Alice S. Whittemore, Laura Baglietto, Valerie McGuire, Christa Stegmaier, Weiva Sieh, Heiko Müller, Volker Arndt, France Labrèche, Yu-Tang Gao, Mark S. Goldberg, Gong Yang, Martine Dumont, John R. McLaughlin, Arndt Hartmann, Arif B. Ekici, Matthias W. Beckmann, Catherine M. Phelan, Michael P. Lux, Jenny Permuth-Wey, Bernard Peissel, Thomas A. Sellers, Filomena Ficarazzi, Monica Barile, Argyrios Ziogas, Alan Ashworth, Aleksandra Gentry-Maharaj, Michael Jones, Susan J. Ramus, Nick Orr, Usha Menon, Celeste L. Pearce, Thomas Brüning, Malcolm C. Pike, Yon-Dschun Ko, Jolanta Lissowska, Jonine Figueroa, Jolanta Kupryjanczyk, Stephen J. Chanock, Agnieszka Dansonka-Mieszkowska, Arja Jukkola-Vuorinen, Iwona K. Rzepecka, Katri Pylkäs, Mariusz Bidzinski, Saila Kauppila, Antoinette Hollestelle, Caroline Seynaeve, Rob A. E. M. Tollenaar, Katarzyna Durda, Katarzyna Jaworska, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Natalia N. Antonenkova, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Artitaya Lophatananon, Pornthep Siriwanarangsan, Sarah Stewart-Brown, Nina Ditsch, Peter Lichtner, Rita K. Schmutzler, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Chiu-Chen Tseng, Daniel O. Stram, David van den Berg, Cheng Har Yip, M. Kamran Ikram, Yew-Ching Teh, Hui Cai, Wei Lu, Lisa B. Signorello, Qiuyin Cai, Dong-Young Noh, Keun-Young Yoo, Hui Miao, Philip Tsau-Choong Iau, Yik Ying Teo, James McKay, Charles Shapiro, Foluso Ademuyiwa, George Fountzilas, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Catherine S. Healey, Craig Luccarini, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Timothy R. Rebbeck, Marion Piedmonte, Christian F. Singer, Eitan Friedman, Mads Thomassen, Kenneth Offit, Thomas v. O. Hansen, Susan L. Neuhausen, Csilla I. Szabo, Ignacio Blanco, Judy Garber, Steven A. Narod, Jeffrey N. Weitzel, Marco Montagna, Edith Olah, Andrew K. Godwin, Drakoulis Yannoukakos, David E. Goldgar, Trinidad Caldes, Evgeny N. Imyanitov, Laima Tihomirova, Banu K. Arun, Ian Campbell, Arjen R. Mensenkamp, Christi J. van Asperen, Kees E. P. van Roozendaal, Hanne Meijers-Heijboer, J. Margriet Collée, Jan C. Oosterwijk, Maartje J. Hooning, Matti A. Rookus, Rob B. van der Luijt, Theo A. Mvan Os, D. Gareth Evans, Debra Frost, Elena Fineberg, Julian Barwell, Lisa Walker, M. John Kennedy, Radka Platte, Rosemarie Davidson, Steve D. Ellis, Trevor Cole, Brigitte Bressac-de Paillerets, Bruno Buecher, Francesca Damiola, Laurence Faivre, Marc Frenay, Olga M. Sinilnikova, Olivier Caron, Sophie Giraud, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Aleksandra Toloczko-Grabarek, Jacek Gronwald, Tomasz Byrski, Amanda B. Spurdle, Bernardo Bonanni, Daniela Zaffaroni, Giuseppe Giannini, Loris Bernard, Riccardo Dolcetti, Siranoush Manoukian, Norbert Arnold, Christoph Engel, Helmut Deissler, Kerstin Rhiem, Dieter Niederacher, Hansjoerg Plendl, Christian Sutter, Barbara Wappenschmidt, Ake Borg, Beatrice Melin, Johanna Rantala, Maria Soller, Katherine L. Nathanson, Susan M. Domchek, Gustavo C. Rodriguez, Ritu Salani, Daphne Gschwantler Kaulich, Muy-Kheng Tea, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Torben A. Kruse, Uffe Birk Jensen, Mark Robson, Anne-Marie Gerdes, Bent Ejlertsen, Lenka Foretova, Sharon A. Savage, Jenny Lester, Penny Soucy, Karoline B. Kuchenbaecker, Curtis Olswold, Julie M. Cunningham, Susan Slager, Vernon S. Pankratz, Ed Dicks, Sunil R. Lakhani, Fergus J. Couch, Per Hall, Alvaro N. A. Monteiro, Simon A. Gayther, Paul D. P. Pharoah, Roger R. Reddel, Ellen L. Goode, Mark H. Greene, Douglas F. Easton, Andrew Berchuck, Antonis C. Antoniou, Georgia Chenevix-Trench, Alison M. Dunning

Date Published: 1st Apr 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Authors: Juliet D. French, Maya Ghoussaini, Stacey L. Edwards, Kerstin B. Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel J. Maranian, Martin O’Reilly, Kristine M. Hillman, Joshua A. Betts, Thomas Carroll, Peter J. Bailey, Ed Dicks, Jonathan Beesley, Jonathan Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas W. Knoblauch, Constance Chen, Peter Kraft, Daniel Barnes, Anna González-Neira, M. Rosario Alonso, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K. Bolla, Qin Wang, John L. Hopper, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Christian R. Loehberg, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Zoe Aitken, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Frederik 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 Ignacio Arias Perez, Javier Benitez, Hoda Anton-Culver, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K. Schmutzler, Christoph Engel, Hiltrud Brauch, Ute Hamann, Christina Justenhoven, Kirsimari Aaltonen, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Natalia V. Bogdanova, Natalia N. Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Anna H. Wu, Chiu-Chen Tseng, David van den Berg, Daniel O. Stram, Diether Lambrechts, Stephanie Peeters, Ann Smeets, Giuseppe Floris, Jenny Chang-Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Domenico Sardella, Fergus J. Couch, Xianshu Wang, Vernon S. Pankratz, Adam Lee, Graham G. Giles, Gianluca Severi, Laura Baglietto, 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, Char-Hong Ng, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Daniel Klevebring, Nils Schoof, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Madeleine Tilanus-Linthorst, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Sabapathy P. Balasubramanian, William Blot, Lisa B. Signorello, Qiuyin Cai, Paul D. P. Pharoah, Catherine S. Healey, Mitul Shah, Karen A. Pooley, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Jen-Hwei Sng, Xueling Sim, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, James McKay, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Andrew K. Godwin, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shou-Tung Chen, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A. J. Ponder, Heli Nevanlinna, Melissa A. Brown, Georgia Chenevix-Trench, Douglas F. Easton, Alison M. Dunning

Date Published: 1st Apr 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

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 \times 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 \times 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 \times 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\times10(-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.

Authors: Fergus J. Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B. Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, Mia M. Gaudet, Ed Dicks, Matthew Kosel, Sue Healey, Olga M. Sinilnikova, Adam Lee, François Bacot, Daniel Vincent, Frans B. L. Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, Anna Jakubowska, Paolo Radice, Rita Katharina Schmutzler, Susan M. Domchek, Marion Piedmonte, Christian F. Singer, Eitan Friedman, Mads Thomassen, Thomas v. O. Hansen, Susan L. Neuhausen, Csilla I. Szabo, Ignacio Blanco, Mark H. Greene, Beth Y. Karlan, Judy Garber, Catherine M. Phelan, Jeffrey N. Weitzel, Marco Montagna, Edith Olah, Irene L. Andrulis, Andrew K. Godwin, Drakoulis Yannoukakos, David E. Goldgar, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Mary Beth Terry, Mary B. Daly, Elizabeth J. van Rensburg, Ute Hamann, Susan J. Ramus, Amanda Ewart Toland, Maria A. Caligo, Olufunmilayo I. Olopade, Nadine Tung, Kathleen Claes, Mary S. Beattie, Melissa C. Southey, Evgeny N. Imyanitov, Marc Tischkowitz, Ramunas Janavicius, Esther M. John, Ava Kwong, Orland Diez, Judith Balmaña, Rosa B. Barkardottir, Banu K. Arun, Gad Rennert, Soo-Hwang Teo, Patricia A. Ganz, Ian Campbell, Annemarie H. van der Hout, Carolien H. M. van Deurzen, Caroline Seynaeve, Encarna B. Gómez Garcia, Flora E. van Leeuwen, Hanne E. J. Meijers-Heijboer, Johannes J. P. Gille, Margreet G. E. M. Ausems, Marinus J. Blok, Marjolijn J. L. Ligtenberg, Matti A. Rookus, Peter Devilee, Senno Verhoef, Theo A. M. van Os, Juul T. Wijnen, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D. Gareth Evans, Louise Izatt, Rosalind A. Eeles, Julian Adlard, Diana M. Eccles, Jackie Cook, Carole Brewer, Fiona Douglas, Shirley Hodgson, Patrick J. Morrison, Lucy E. Side, Alan Donaldson, Catherine Houghton, Mark T. Rogers, Huw Dorkins, Jacqueline Eason, Helen Gregory, Emma McCann, Alex Murray, Alain Calender, Agnès Hardouin, Pascaline Berthet, Capucine Delnatte, Catherine Nogues, Christine Lasset, Claude Houdayer, Dominique Leroux, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Hagay Sobol, Isabelle Coupier, Laurence Venat-Bouvet, Laurent Castera, Marion Gauthier-Villars, Mélanie Léoné, Pascal Pujol, Sylvie Mazoyer, Yves-Jean Bignon, Elżbieta Złowocka-Perłowska, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska, Tomasz Huzarski, Amanda B. Spurdle, Alessandra Viel, Bernard Peissel, Bernardo Bonanni, Giulia Melloni, Laura Ottini, Laura Papi, Liliana Varesco, Maria Grazia Tibiletti, Paolo Peterlongo, Sara Volorio, Siranoush Manoukian, Valeria Pensotti, Norbert Arnold, Christoph Engel, Helmut Deissler, Dorothea Gadzicki, Andrea Gehrig, Karin Kast, Kerstin Rhiem, Alfons Meindl, Dieter Niederacher, Nina Ditsch, Hansjoerg Plendl, Sabine Preisler-Adams, Stefanie Engert, Christian Sutter, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Bernhard H. F. Weber, Brita Arver, Marie Stenmark-Askmalm, Niklas Loman, Richard Rosenquist, Zakaria Einbeigi, Katherine L. Nathanson, Timothy R. Rebbeck, Stephanie V. Blank, David E. Cohn, Gustavo C. Rodriguez, Laurie Small, Michael Friedlander, Victoria L. Bae-Jump, Anneliese Fink-Retter, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy-Kheng Tea, Noralane M. Lindor, Bella Kaufman, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Anne-Marie Gerdes, Inge Sokilde Pedersen, Sanne Traasdahl Moeller, Torben A. Kruse, Uffe Birk Jensen, Joseph Vijai, Kara Sarrel, Mark Robson, Noah Kauff, Anna Marie Mulligan, Gord Glendon, Hilmi Ozcelik, Bent Ejlertsen, Finn C. Nielsen, Lars Jønson, Mette K. Andersen, Yuan Chun Ding, Linda Steele, Lenka Foretova, Alex Teulé, Conxi Lazaro, Joan Brunet, Miquel Angel Pujana, Phuong L. Mai, Jennifer T. Loud, Christine Walsh, Jenny Lester, Sandra Orsulic, Steven A. Narod, Josef Herzog, Sharon R. Sand, Silvia Tognazzo, Simona Agata, Tibor Vaszko, JoEllen Weaver, Alexandra V. Stavropoulou, Saundra S. Buys, Atocha Romero, Miguel de La Hoya, Kristiina Aittomäki, Taru A. Muranen, Mercedes Duran, Wendy K. Chung, Adriana Lasa, Cecilia M. Dorfling, Alexander Miron, Javier Benitez, Leigha Senter, Dezheng Huo, Salina B. Chan, Anna P. Sokolenko, Jocelyne Chiquette, Laima Tihomirova, Tara M. Friebel, Bjarni A. Agnarsson, Karen H. Lu, Flavio Lejbkowicz, Paul A. James, Per Hall, Alison M. Dunning, Daniel Tessier, Julie Cunningham, Susan L. Slager, Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S. Pankratz, Kenneth Offit, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou

Date Published: 27th Mar 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%-100%] and specificity was estimated at 100% (95% CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS.

Authors: Lucia Guidugli, Vernon S. Pankratz, Namit Singh, James Thompson, Catherine A. Erding, Christoph Engel, Rita Schmutzler, Susan Domchek, Katherine Nathanson, Paolo Radice, Christian Singer, Patricia N. Tonin, Noralane M. Lindor, David E. Goldgar, Fergus J. Couch

Date Published: 2nd Jan 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

INTRODUCTION While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancerr risk in patients from high risk families that tested negative for BRCA1/2 mutations. METHODS A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. RESULTS The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. CONCLUSIONS Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Authors: Kerstin Rhiem, Christoph Engel, Monika Graeser, Silke Zachariae, Karin Kast, Marion Kiechle, Nina Ditsch, Wolfgang Janni, Christoph Mundhenke, Michael Golatta, Dominic Varga, Sabine Preisler-Adams, Tilman Heinrich, Ulrich Bick, Dorothea Gadzicki, Susanne Briest, Alfons Meindl, Rita K. Schmutzler

Date Published: 1st Dec 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

Authors: C. Fischer, C. Engel, C. Sutter, S. Zachariae, R. Schmutzler, A. Meindl, S. Heidemann, T. Grimm, T. O. Goecke, I. Debatin, D. Horn, P. Wieacker, D. Gadzicki, K. Becker, D. Schäfer, F. Stock, T. Voigtländer

Date Published: 1st Nov 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

BACKGROUND Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carryingg these variants. We previously showed that variant BRCA1 c.5096G\textgreaterA p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. METHODS Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G\textgreaterA p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C\textgreaterT p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). RESULTS Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G\textgreaterA p.Arg1699Gln variant carriers had family histories that were less ’BRCA1-like’ than BRCA1 c.5095C\textgreaterT p.Arg1699Trp mutation carriers (p\textless0.00001), but more ’BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G \textgreaterA p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. CONCLUSIONS Our results provide substantial evidence that the BRCA1 c.5096G\textgreaterA p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

Authors: Amanda B. Spurdle, Phillip J. Whiley, Bryony Thompson, Bingjian Feng, Sue Healey, Melissa A. Brown, Christopher Pettigrew, Christi J. van Asperen, Margreet G. E. M. Ausems, Anna A. Kattentidt-Mouravieva, Ans M. W. van den Ouweland, Annika Lindblom, Maritta H. Pigg, Rita K. Schmutzler, Christoph Engel, Alfons Meindl, Sandrine Caputo, Olga M. Sinilnikova, Rosette Lidereau, Fergus J. Couch, Lucia Guidugli, Thomas Overeem van Hansen, Mads Thomassen, Diana M. Eccles, Kathy Tucker, Javier Benitez, Susan M. Domchek, Amanda E. Toland, Elizabeth J. van Rensburg, Barbara Wappenschmidt, Åke Borg, Maaike P. G. Vreeswijk, David E. Goldgar

Date Published: 12th Aug 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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