Publications

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

Abstract (Expand)

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 \times 10(-20)), ER-negative BC (P=1.1 \times 10(-13)), BRCA1-associated BC (P=7.7 \times 10(-16)) and triple negative BC (P-diff=2 \times 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 \times 10(-3)) and ABHD8 (P\textless2 \times 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3’-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

Authors: Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas v. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de La Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim de Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. van’t Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, Simon A. Gayther

Date Published: 1st Nov 2016

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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)

INTRODUCTION Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNAA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Authors: Sophie Blein, Claire Bardel, Vincent Danjean, Lesley McGuffog, Sue Healey, Daniel Barrowdale, Andrew Lee, Joe Dennis, Karoline B. Kuchenbaecker, Penny Soucy, Mary Beth Terry, Wendy K. Chung, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Susan L. Neuhausen, Yuan Chun Ding, Anne-Marie Gerdes, Bent Ejlertsen, Finn C. Nielsen, Thomas vO Hansen, Ana Osorio, Javier Benitez, Raquel Andrés Conejero, Ena Segota, Jeffrey N. Weitzel, Margo Thelander, Paolo Peterlongo, Paolo Radice, Valeria Pensotti, Riccardo Dolcetti, Bernardo Bonanni, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Siranoush Manoukian, Liliana Varesco, Gabriele L. Capone, Laura Papi, Laura Ottini, Drakoulis Yannoukakos, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Angela Brady, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Jackie Cook, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Trevor Cole, Andrew K. Godwin, Claudine Isaacs, Kathleen Claes, Kim de Leeneer, Alfons Meindl, Andrea Gehrig, Barbara Wappenschmidt, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Rita K. Schmutzler, Sabine Preisler-Adams, Nadja Bogdanova Markov, Shan Wang-Gohrke, Antoine de Pauw, Cédrick Lefol, Christine Lasset, Dominique Leroux, Etienne Rouleau, Francesca Damiola, Hélène Dreyfus, Laure Barjhoux, Lisa Golmard, Nancy Uhrhammer, Valérie Bonadona, Valérie Sornin, Yves-Jean Bignon, Jonathan Carter, Linda van Le, Marion Piedmonte, Paul A. DiSilvestro, Miguel de La Hoya, Trinidad Caldes, Heli Nevanlinna, Kristiina Aittomäki, Agnes Jager, Ans Mw van den Ouweland, Carolien M. Kets, Cora M. Aalfs, Flora E. van Leeuwen, Frans Bl Hogervorst, Hanne Ej Meijers-Heijboer, Jan C. Oosterwijk, Kees Ep van Roozendaal, Matti A. Rookus, Peter Devilee, Rob B. van der Luijt, Edith Olah, Orland Diez, Alex Teulé, Conxi Lazaro, Ignacio Blanco, Jesús Del Valle, Anna Jakubowska, Grzegorz Sukiennicki, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Bjarni A. Agnarsson, Christine Maugard, Alberto Amadori, Marco Montagna, Manuel R. Teixeira, Amanda B. Spurdle, William Foulkes, Curtis Olswold, Noralane M. Lindor, Vernon S. Pankratz, Csilla I. Szabo, Anne Lincoln, Lauren Jacobs, Marina Corines, Mark Robson, Joseph Vijai, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Mark H. Greene, Phuong L. Mai, Gad Rennert, Evgeny N. Imyanitov, Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Sandrine Tchatchou, Amanda Ewart Toland, Inge Sokilde Pedersen, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Jamal Zidan, Yael Laitman, Annika Lindblom, Beatrice Melin, Brita Arver, Niklas Loman, Richard Rosenquist, Olufunmilayo I. Olopade, Robert L. Nussbaum, Susan J. Ramus, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Gillian Mitchell, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Dominique Stoppa-Lyonnet, Gilles Thomas, Jacques Simard, Fergus J. Couch, Kenneth Offit, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Sylvie Mazoyer, Catherine M. Phelan, Olga M. Sinilnikova, David G. Cox

Date Published: 1st Dec 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5’ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Authors: Hatef Darabi, Karen McCue, Jonathan Beesley, Kyriaki Michailidou, Silje Nord, Siddhartha Kar, Keith Humphreys, Deborah Thompson, Maya Ghoussaini, Manjeet K. Bolla, Joe Dennis, Qin Wang, Sander Canisius, Christopher G. Scott, Carmel Apicella, John L. Hopper, Melissa C. Southey, Jennifer Stone, Annegien Broeks, Marjanka K. Schmidt, Rodney J. Scott, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Arif B. Ekici, Peter A. Fasching, Katharina Heusinger, Isabel Dos-Santos-Silva, Julian Peto, Ian Tomlinson, Elinor J. Sawyer, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L. Neuhausen, Volker Arndt, Hermann Brenner, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Norbert Arnold, Hiltrud Brauch, Ute Hamann, Jenny Chang-Claude, Sofia Khan, Heli Nevanlinna, Hidemi Ito, Keitaro Matsuo, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Veli-Matti Kosma, Arto Mannermaa, Chiu-Chen Tseng, Anna H. Wu, Giuseppe Floris, Diether Lambrechts, Anja Rudolph, Paolo Peterlongo, Paolo Radice, Fergus J. Couch, Celine Vachon, Graham G. Giles, Catriona McLean, Roger L. Milne, Pierre-Antoine Dugué, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Brian E. Henderson, Mark S. Goldberg, Jacques Simard, Soo H. Teo, Shivaani Mariapun, Åslaug Helland, Vilde Haakensen, Wei Zheng, Alicia Beeghly-Fadiel, Rulla Tamimi, Arja Jukkola-Vuorinen, Robert Winqvist, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Robert A. E. M. Tollenaar, Jonine Figueroa, Montserrat García-Closas, Kamila Czene, Maartje J. Hooning, Madeleine Tilanus-Linthorst, Jingmei Li, Yu-Tang Gao, Xiao-Ou Shu, Angela Cox, Simon S. Cross, Robert Luben, Kay-Tee Khaw, Ji-Yeob Choi, Daehee Kang, Mikael Hartman, Wei Yen Lim, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, James McKay, Suleeporn Sangrajrang, Amanda E. Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Jyh-Cherng Yu, Argyrios Ziogas, Minouk J. Schoemaker, Anthony Swerdlow, Anne-Lise Borresen-Dale, Vessela Kristensen, Juliet D. French, Stacey L. Edwards, Alison M. Dunning, Douglas F. Easton, Per Hall, Georgia Chenevix-Trench

Date Published: 1st Jul 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p = 2.61 \times 10(-9) adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p \textless 0.0001; second validation round with 189 BC case and 189 controls: p \textless 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early-stage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age \textless 50, AUC = 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.

Authors: Rongxi Yang, Katrin Pfütze, Manuela Zucknick, Christian Sutter, Barbara Wappenschmidt, Frederik Marme, Bin Qu, Katarina Cuk, Christoph Engel, Sarah Schott, Andreas Schneeweiss, Hermann Brenner, Rainer Claus, Christoph Plass, Peter Bugert, Markus Hoth, Christof Sohn, Rita Schmutzler, Claus R. Bartram, Barbara Burwinkel

Date Published: 15th Apr 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriersers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 \times 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2’, RHR = 1.38; 95% CI, 1.22-1.55; P = 6 \times 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 \times 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1’; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 \times 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Authors: Timothy R. Rebbeck, Nandita Mitra, Fei Wan, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Sylvie Mazoyer, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou, Katherine L. Nathanson, Yael Laitman, Anya Kushnir, Shani Paluch-Shimon, Raanan Berger, Jamal Zidan, Eitan Friedman, Hans Ehrencrona, Marie Stenmark-Askmalm, Zakaria Einbeigi, Niklas Loman, Katja Harbst, Johanna Rantala, Beatrice Melin, Dezheng Huo, Olufunmilayo I. Olopade, Joyce Seldon, Patricia A. Ganz, Robert L. Nussbaum, Salina B. Chan, Kunle Odunsi, Simon A. Gayther, Susan M. Domchek, Banu K. Arun, Karen H. Lu, Gillian Mitchell, Beth Y. Karlan, Christine Walsh, Jenny Lester, Andrew K. Godwin, Harsh Pathak, Eric Ross, Mary B. Daly, Alice S. Whittemore, Esther M. John, Alexander Miron, Mary Beth Terry, Wendy K. Chung, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Susan L. Neuhausen, Yuan Chun Ding, Bent Ejlertsen, Anne-Marie Gerdes, Thomas v. O. Hansen, Teresa Ramón y Cajal, Ana Osorio, Javier Benitez, Javier Godino, Maria-Isabel Tejada, Mercedes Duran, Jeffrey N. Weitzel, Kristie A. Bobolis, Sharon R. Sand, Annette Fontaine, Antonella Savarese, Barbara Pasini, Bernard Peissel, Bernardo Bonanni, Daniela Zaffaroni, Francesca Vignolo-Lutati, Giulietta Scuvera, Giuseppe Giannini, Loris Bernard, Maurizio Genuardi, Paolo Radice, Riccardo Dolcetti, Siranoush Manoukian, Valeria Pensotti, Viviana Gismondi, Drakoulis Yannoukakos, Florentia Fostira, Judy Garber, Diana Torres, Muhammad Usman Rashid, Ute Hamann, Susan Peock, Debra Frost, Radka Platte, D. Gareth Evans, Rosalind Eeles, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Shirley Hodgson, Patrick J. Morrison, Lisa Walker, Mary E. Porteous, M. John Kennedy, Louise Izatt, Julian Adlard, Alan Donaldson, Steve Ellis, Priyanka Sharma, Rita Katharina Schmutzler, Barbara Wappenschmidt, Alexandra Becker, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Stefanie Engert, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Christoph Mundhenke, Dieter Niederacher, Markus Fleisch, Christian Sutter, C. R. Bartram, Nicola Dikow, Shan Wang-Gohrke, Dorothea Gadzicki, Doris Steinemann, Karin Kast, Marit Beer, Raymonda Varon-Mateeva, Andrea Gehrig, Bernhard H. Weber, Dominique Stoppa-Lyonnet, Claude Houdayer, Muriel Belotti, Marion Gauthier-Villars, Francesca Damiola, Nadia Boutry-Kryza, Christine Lasset, Hagay Sobol, Jean-Philippe Peyrat, Danièle Muller, Jean-Pierre Fricker, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, Catherine Nogues, Etienne Rouleau, Claudine Isaacs, Anne de Paepe, Bruce Poppe, Kathleen Claes, Kim de Leeneer, Marion Piedmonte, Gustavo Rodriguez, Katie Wakely, John Boggess, Stephanie V. Blank, Jack Basil, Masoud Azodi, Kelly-Anne Phillips, Trinidad Caldes, Miguel de La Hoya, Atocha Romero, Heli Nevanlinna, Kristiina Aittomäki, Annemarie H. van der Hout, Frans B. L. Hogervorst, Senno Verhoef, J. Margriet Collée, Caroline Seynaeve, Jan C. Oosterwijk, Johannes J. P. Gille, Juul T. Wijnen, Encarna B. Gómez Garcia, Carolien M. Kets, Margreet G. E. M. Ausems, Cora M. Aalfs, Peter Devilee, Arjen R. Mensenkamp, Ava Kwong, Edith Olah, Janos Papp, Orland Diez, Conxi Lazaro, Esther Darder, Ignacio Blanco, Mónica Salinas, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Grzegorz Sukiennicki, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Aleksandra Toloczko-Grabarek, Elżbieta Złowocka-Perłowska, Janusz Menkiszak, Adalgeir Arason, Rosa B. Barkardottir, Jacques Simard, Rachel Laframboise, Marco Montagna, Simona Agata, Elisa Alducci, Ana Peixoto, Manuel R. Teixeira, Amanda B. Spurdle, Min Hyuk Lee, Sue K. Park, Sung-Won Kim, Tara M. Friebel, Fergus J. Couch, Noralane M. Lindor, Vernon S. Pankratz, Lucia Guidugli, Xianshu Wang, Marc Tischkowitz, Lenka Foretova, Joseph Vijai, Kenneth Offit, Mark Robson, Rohini Rau-Murthy, Noah Kauff, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Mark H. Greene, Phuong L. Mai, Evgeny N. Imyanitov, Amanda Ewart Toland, Leigha Senter, Anders Bojesen, Inge Sokilde Pedersen, Anne-Bine Skytte, Lone Sunde, Mads Thomassen, Sanne Traasdahl Moeller, Torben A. Kruse, Uffe Birk Jensen, Maria Adelaide Caligo, Paolo Aretini, Soo-Hwang Teo, Christina G. Selkirk, Peter J. Hulick, Irene Andrulis

Date Published: 7th Apr 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values \textgreater 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Authors: Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Vernon S. Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Català, Joan Brunet, Lidia Feliubadaló, Eva Tornero, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K. Arun, Amanda E. Toland, Beth Y. Karlan, Christine Walsh, Jenny Lester, Mark H. Greene, Phuong L. Mai, Robert L. Nussbaum, Irene L. Andrulis, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Rosa B. Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom van Maerken, Orland Díez, Thomas V. Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de La Hoya, Trinidad Caldés, Alison M. Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R. Teixeira, Frans B. L. Hogervorst, Annemarie H. van der Hout, Caroline Seynaeve, Rob B. van der Luijt, Marjolijn J. L. Ligtenberg, Peter Devilee, Juul T. Wijnen, Matti A. Rookus, Hanne E. J. Meijers-Heijboer, Marinus J. Blok, Ans M. W. van den Ouweland, Cora M. Aalfs, Gustavo C. Rodriguez, Kelly-Anne A. Phillips, Marion Piedmonte, Stacy R. Nerenstone, Victoria L. Bae-Jump, David M. O’Malley, Elena S. Ratner, Rita K. Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J. Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A. Kruse, Lenka Foretova, Paolo Peterlongo, Loris Bernard, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, Esther M. John, Alex Miron, Susan L. Neuhausen, Mary Beth Terry, Wendy K. Chung, Mary B. Daly, David E. Goldgar, Ramunas Janavicius, Cecilia M. Dorfling, Elisabeth J. van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Andrew K. Godwin, Edith Olah, Steven A. Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N. Imyanitov, Ute Hamann, Amanda B. Spurdle, Sue Healey, Jeffrey N. Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M. Sinilnikova, Christopher A. Maxwell, Joseph Vijai, Mark Robson, Noah Kauff, Marina J. Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F. Easton, Kenneth Offit, Georgia Chenevix-Trench, Fergus J. Couch, Antonis C. Antoniou, Miguel Angel Pujana

Date Published: 1st Apr 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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