Publications

13 Publications visible to you, out of a total of 13

Abstract (Expand)

OBJECTIVE Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3’ UTR microRNA binding site, based on suggested associations with increased ovariann and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

Authors: Antoinette Hollestelle, Frederieke H. van der Baan, Andrew Berchuck, Sharon E. Johnatty, Katja K. Aben, Bjarni A. Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Antonis C. Antoniou, Carmel Apicella, Volker Arndt, Norbert Arnold, Banu K. Arun, Brita Arver, Alan Ashworth, Laura Baglietto, Rosemary Balleine, Elisa V. Bandera, Daniel Barrowdale, Yukie T. Bean, Lars Beckmann, Matthias W. Beckmann, Javier Benitez, Andreas Berger, Raanan Berger, Benoit Beuselinck, Maria Bisogna, Line Bjorge, Carl Blomqvist, Natalia V. Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Joan Brunet, Thomas Brüning, Agnieszka Budzilowska, Clareann H. Bunker, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jenny Chang-Claude, Stephen J. Chanock, Kathleen B. M. Claes, J. Margriet Collée, Linda S. Cook, Fergus J. Couch, Angela Cox, Daniel Cramer, Simon S. Cross, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Miguel de La Hoya, Anna deFazio, Joseph Dennis, Peter Devilee, Ed M. Dicks, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Isabel Dos Santos Silva, Andreas Du Bois, Martine Dumont, Alison M. Dunning, Mercedes Duran, Douglas F. Easton, Diana Eccles, Robert P. Edwards, Hans Ehrencrona, Bent Ejlertsen, Arif B. Ekici, Steve D. Ellis, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Annette Fontaine, Stefano Fortuzzi, Florentia Fostira, Brooke L. Fridley, Tara Friebel, Eitan Friedman, Grace Friel, Debra Frost, Judy Garber, Montserrat García-Closas, Simon A. Gayther, Aleksandra Gentry-Maharaj, Anne-Marie Gerdes, Graham G. Giles, Rosalind Glasspool, Gord Glendon, Andrew K. Godwin, Marc T. Goodman, Martin Gore, Mark H. Greene, Mervi Grip, Jacek Gronwald, Daphne Gschwantler Kaulich, Pascal Guénel, Starr R. Guzman, Lothar Haeberle, Christopher A. Haiman, Per Hall, Sandra L. Halverson, Ute Hamann, Thomas v. O. Hansen, Philipp Harter, Jaana M. Hartikainen, Sue Healey, Alexander Hein, Florian Heitz, Brian E. Henderson, Josef Herzog, Michelle A. T Hildebrandt, Claus K. Høgdall, Estrid Høgdall, Frans B. L. Hogervorst, John L. Hopper, Keith Humphreys, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska, Allan Jensen, Uffe Birk Jensen, Nichola Johnson, Arja Jukkola-Vuorinen, Maria Kabisch, Beth Y. Karlan, Vesa Kataja, Noah Kauff, Linda E. Kelemen, Michael J. Kerin, Lambertus A. Kiemeney, Susanne K. Kjaer, Julia A. Knight, Jacoba P. Knol-Bout, Irene Konstantopoulou, Veli-Matti Kosma, Camilla Krakstad, Vessela Kristensen, Karoline B. Kuchenbaecker, Jolanta Kupryjanczyk, Yael Laitman, Diether Lambrechts, Sandrina Lambrechts, Melissa C. Larson, Adriana Lasa, Pierre Laurent-Puig, Conxi Lazaro, Nhu D. Le, Loic Le Marchand, Arto Leminen, Jenny Lester, Douglas A. Levine, Jingmei Li, Dong Liang, Annika Lindblom, Noralane Lindor, Jolanta Lissowska, Jirong Long, Karen H. Lu, Jan Lubinski, Lene Lundvall, Galina Lurie, Phuong L. Mai, Arto Mannermaa, Sara Margolin, Frederique Mariette, Frederik Marme, John W. M. Martens, Leon F. A. G. Massuger, Christine Maugard, Sylvie Mazoyer, Lesley McGuffog, Valerie McGuire, Catriona McLean, Iain McNeish, Alfons Meindl, Florence Menegaux, Primitiva Menéndez, Janusz Menkiszak, Usha Menon, Arjen R. Mensenkamp, Nicola Miller, Roger L. Milne, Francesmary Modugno, Marco Montagna, Kirsten B. Moysich, Heiko Müller, Anna Marie Mulligan, Taru A. Muranen, Steven A. Narod, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Sune F. Nielsen, Børge G. Nordestgaard, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Sara H. Olson, Jan C. Oosterwijk, Irene Orlow, Nick Orr, Sandra Orsulic, Ana Osorio, Laura Ottini, James Paul, Celeste L. Pearce, Inge Sokilde Pedersen, Bernard Peissel, Tanja Pejovic, Liisa M. Pelttari, Jo Perkins, Jenny Permuth-Wey, Paolo Peterlongo, Julian Peto, Catherine M. Phelan, Kelly-Anne Phillips, Marion Piedmonte, Malcolm C. Pike, Radka Platte, Joanna Plisiecka-Halasa, Elizabeth M. Poole, Bruce Poppe, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Timothy R. Rebbeck, Malcolm W. R. Reed, Gad Rennert, Harvey A. Risch, Mark Robson, Gustavo C. Rodriguez, Atocha Romero, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo Runnebaum, Ritu Salani, Helga B. Salvesen, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Michael G. Schrauder, Fredrick Schumacher, Ira Schwaab, Giulietta Scuvera, Thomas A. Sellers, Gianluca Severi, Caroline M. Seynaeve, Mitul Shah, Martha Shrubsole, Nadeem Siddiqui, Weiva Sieh, Jacques Simard, Christian F. Singer, Olga M. Sinilnikova, Dominiek Smeets, Christof Sohn, Maria Soller, Honglin Song, Penny Soucy, Melissa C. Southey, Christa Stegmaier, Dominique Stoppa-Lyonnet, Lara Sucheston, Anthony Swerdlow, Ingvild L. Tangen, Muy-Kheng Tea, Manuel R. Teixeira, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Pamela J. Thompson, Laima Tihomirova, Marc Tischkowitz, Amanda Ewart Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Helen Tsimiklis, Nadine Tung, Shelley S. Tworoger, Jonathan P. Tyrer, Celine M. Vachon, Laura J. van ’t Veer, Anne M. van Altena, C. J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Helena C. van Doorn, Els van Nieuwenhuysen, Elizabeth J. van Rensburg, Ignace Vergote, Senno Verhoef, Robert A. Vierkant, Joseph Vijai, Allison F. Vitonis, Anna von Wachenfeldt, Christine Walsh, Qin Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Maren Weischer, Jeffrey N. Weitzel, Caroline Weltens, Nicolas Wentzensen, Alice S. Whittemore, Lynne R. Wilkens, Robert Winqvist, Anna H. Wu, Xifeng Wu, Hannah P. Yang, Daniela Zaffaroni, M. Pilar Zamora, Wei Zheng, Argyrios Ziogas, Georgia Chenevix-Trench, Paul D. P. Pharoah, Matti A. Rookus, Maartje J. Hooning, Ellen L. Goode

Date Published: 1st May 2016

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Brain-derived neurotrophic factor (BDNF) has been discussed to be involved in plasticity processes in the human brain, in particular during aging. Recently, aging and its (neurodegenerative) diseases have increasingly been conceptualized as disconnection syndromes. Here, connectivity changes in neural networks (the connectome) are suggested to be the most relevant and characteristic features for such processes or diseases. To further elucidate the impact of aging on neural networks, we investigated the interaction between plasticity processes, brain connectivity, and healthy aging by measuring levels of serum BDNF and resting-state fMRI data in 25 young (mean age 24.8 +/- 2.7 (SD) years) and 23 old healthy participants (mean age, 68.6 +/- 4.1 years). To identify neural hubs most essentially related to serum BDNF, we applied graph theory approaches, namely the new data-driven and parameter-free approach eigenvector centrality (EC) mapping. The analysis revealed a positive correlation between serum BDNF and EC in the premotor and motor cortex in older participants in contrast to young volunteers, where we did not detect any association. This positive relationship between serum BDNF and EC appears to be specific for older adults. Our results might indicate that the amount of physical activity and learning capacities, leading to higher BDNF levels, increases brain connectivity in (pre)motor areas in healthy aging in agreement with rodent animal studies. Pilot results have to be replicated in a larger sample including behavioral data to disentangle the cause for the relationship between BDNF levels and connectivity.

Authors: K. Mueller, K. Arelin, H. E. Moller, J. Sacher, J. Kratzsch, T. Luck, S. Riedel-Heller, A. Villringer, M. L. Schroeter

Date Published: 2nd Feb 2016

Publication Type: Not specified

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

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)

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 \times 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 \times 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 \times 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.

Authors: Kristen N. Stevens, Zachary Fredericksen, Celine M. Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Jenny Chang-Claude, Alina Vrieling, Dieter Flesch-Janys, Hans-Peter Sinn, Shan Wang-Gohrke, Stefan Nickels, Hiltrud Brauch, Yon-Dschun Ko, Hans-Peter Fischer, Rita K. Schmutzler, Alfons Meindl, Claus R. Bartram, Sarah Schott, Christoph Engel, Andrew K. Godwin, JoEllen Weaver, Harsh B. Pathak, Priyanka Sharma, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Penelope Miron, Drakoulis Yannoukakos, Alexandra Stavropoulou, George Fountzilas, Helen J. Gogas, Ruth Swann, Miriam Dwek, Annie Perkins, Roger L. Milne, Javier Benítez, María Pilar Zamora, José Ignacio Arias Pérez, Stig E. Bojesen, Sune F. Nielsen, Børge G. Nordestgaard, Henrik Flyger, Pascal Guénel, Thérèse Truong, Florence Menegaux, Emilie Cordina-Duverger, Barbara Burwinkel, Frederick Marmé, Andreas Schneeweiss, Christof Sohn, Elinor Sawyer, Ian Tomlinson, Michael J. Kerin, Julian Peto, Nichola Johnson, Olivia Fletcher, Isabel Dos Santos Silva, Peter A. Fasching, Matthias W. Beckmann, Arndt Hartmann, Arif B. Ekici, Artitaya Lophatananon, Kenneth Muir, Puttisak Puttawibul, Surapon Wiangnon, Marjanka K. Schmidt, Annegien Broeks, Linde M. Braaf, Efraim H. Rosenberg, John L. Hopper, Carmel Apicella, Daniel J. Park, Melissa C. Southey, Anthony J. Swerdlow, Alan Ashworth, Nicholas Orr, Minouk J. Schoemaker, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Chia-Ni Hsiung, Ute Hamann, Thomas Dünnebier, Thomas Rüdiger, Hans Ulrich Ulmer, Paul P. Pharoah, Alison M. Dunning, Manjeet K. Humphreys, Qin Wang, Angela Cox, Simon S. Cross, Malcom W. Reed, Per Hall, Kamila Czene, Christine B. Ambrosone, Foluso Ademuyiwa, Helena Hwang, Diana M. Eccles, Montserrat Garcia-Closas, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Peter Devilee, Caroline Seynaeve, Rob A. E. M. Tollenaar, Maartje J. Hooning, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Esther M. John, Alexander Miron, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Matthew L. Kosel, V. S. Pankratz, Susan Slager, Janet E. Olson, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Diether Lambrechts, Sigrid Hatse, Anne-Sophie Dieudonne, Marie-Rose Christiaens, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli-Matti Kosma, Jaana M. Hartikainen, Ylermi Soini, Douglas F. Easton, Fergus J. Couch

Date Published: 1st Apr 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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