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1. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Author: Elena Vigorito, Karoline B Kuchenbaecker, Jonathan Beesley, Julian Adlard, Bjarni A Agnarsson, Irene L Andrulis, Banu K Arun, Laure Barjhoux, Muriel Belotti, Javier Benitez, Andreas Berger, Anders Bojesen, Bernardo Bonanni, Carole Brewer, Trinidad Caldes, Maria A Caligo, Ian Campbell, Salina B Chan, Kathleen B M Claes, David E Cohn, Jackie Cook, Mary B Daly, Francesca Damiola, Rosemarie Davidson, Antoine de Pauw, Capucine Delnatte, Orland Diez, Susan M Domchek, Martine Dumont, Katarzyna Durda, Bernd Dworniczak, Douglas F Easton, Diana Eccles, Christina Edwinsdotter Ardnor, Ros Eeles, Bent Ejlertsen, Steve Ellis, D Gareth Evans, Lidia Feliubadalo, Florentia Fostira, William D Foulkes, Eitan Friedman, Debra Frost, Pragna Gaddam, Patricia A Ganz, Judy Garber, Vanesa Garcia-Barberan, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Sophie Giraud, Andrew K Godwin, David E Goldgar, Christopher R Hake, Thomas V O Hansen, Sue Healey, Shirley Hodgson, Frans B L Hogervorst, Claude Houdayer, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Lauren Jacobs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M John, Joseph Vijai, Beth Y Karlan, Karin Kast, KConFab Investigators, Sofia Khan, Ava Kwong, Yael Laitman, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jan Lubinski, Phuong L Mai, Siranoush Manoukian, Sylvie Mazoyer, Alfons Meindl, Arjen R Mensenkamp, Marco Montagna, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Kai-Ren Ong, Ana Osorio, Sue Kyung Park, Ylva Paulsson-Karlsson, Inge Sokilde Pedersen, Bernard Peissel, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Marion Piedmonte, Bruce Poppe, Miquel Angel Pujana, Paolo Radice, Gad Rennert, Gustavo C Rodriguez, Matti A Rookus, Eric A Ross, Rita Katharina Schmutzler, Jacques Simard, Christian F Singer, Thomas P Slavin, Penny Soucy, Melissa Southey, Doris Steinemann, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Csilla I Szabo, Muy-Kheng Tea, Manuel R Teixeira, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Athanassios Vratimos, Jeffrey N Weitzel, Lesley McGuffog, Judy Kirk, Amanda Ewart Toland, Ute Hamann, Noralane Lindor, Susan J Ramus, Mark H Greene, Fergus J Couch, Kenneth Offit, Paul D P Pharoah, Georgia Chenevix-Trench, and Antonis C Antoniou
Subjects: Medicine, Science
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
Published: 2016
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2. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Author: 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, 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, BCFR, 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, SWE-BRCA, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N Imyanitov, Ute Hamann, kConFab Investigators, Amanda B Spurdle, Sue Healey, Jeffrey N Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, GEMO, 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, and Miguel Angel Pujana
Subjects: Medicine, Science
Abstract: 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 > 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.
Published: 2015
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3. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Author: Ana Osorio, Roger L Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de la Hoya, Mercedes Duran, Orland Díez, Teresa Ramón Y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, SWE-BRCA, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I Olopade, Mary S Beattie, Susan M Domchek, Katherine Nathanson, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Christine Walsh, Jenny Lester, Esther M John, Alice S Whittemore, Mary B Daly, Melissa Southey, John Hopper, Mary B Terry, Saundra S Buys, Ramunas Janavicius, Cecilia M Dorfling, Elizabeth J van Rensburg, Linda Steele, Susan L Neuhausen, Yuan Chun Ding, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belén Herráez, Leticia Thais Moreno, Jeffrey N Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodríguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A Rookus, Theo A M van Os, Lizet van der Kolk, J L de Lange, Hanne E J Meijers-Heijboer, A H van der Hout, Christi J van Asperen, Encarna B Gómez Garcia, Nicoline Hoogerbrugge, J Margriet Collée, Carolien H M van Deurzen, Rob B van der Luijt, Peter Devilee, HEBON, Edith Olah, Conxi Lázaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R Teixeira, Sue Healey, KConFab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M Phelan, Mark H Greene, Phuong L Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F Easton, Kenneth Offit, Fergus J Couch, Georgia Chenevix-Trench, Antonis C Antoniou, and Javier Benitez
Subjects: Genetics, QH426-470
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p
Published: 2014
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4. Identifying a highly-aggressive DCIS subgroup by studying intra-individual DCIS heterogeneity among invasive breast cancer patients.

Author: Dana Pape-Zambito, Zhengyu Jiang, Hong Wu, Karthik Devarajan, Carolyn M Slater, Kathy Q Cai, Arthur Patchefsky, Mary B Daly, and Xiaowei Chen
Subjects: Medicine, Science
Abstract: The heterogeneity among multiple ductal carcinoma in situ (DCIS) lesions within the same patient also diagnosed with invasive ductal carcinoma (IDC) has not been well evaluated, leaving research implications of intra-individual DCIS heterogeneity yet to be explored. In this study formalin-fixed paraffin embedded sections from 36 patients concurrently diagnosed with DCIS and IDC were evaluated by immunohistochemistry. Ten DCIS lesions from each patient were then randomly selected and scored. Our results showed that expression of PR, HER2, Ki-67, and p16 varied significantly within DCIS lesions from a single patient (P
Published: 2014
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5. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

Author: 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, kConFab Investigators, Paolo Radice, Rita Katharina Schmutzler, SWE-BRCA, Susan M Domchek, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Ontario Cancer Genetics Network, 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, HEBON, EMBRACE, 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, GEMO Study Collaborators, 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, BCFR, 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, and CIMBA
Subjects: Genetics, QH426-470
Abstract: 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 × 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 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 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 = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013
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6. Identifying putative breast cancer-associated long intergenic non-coding RNA loci by high density SNP array analysis

Author: Zhengyu eJiang, Yan eZhou, Karthik eDevarajan, Carolyn M Slater, Mary B Daly, and Xiaowei eChen
Subjects: breast cancer, SNP array, Non-coding RNA (ncRNA), Long intergenic non-coding RNA (lincRNA), copy number variation (CNV), Genetics, QH426-470
Abstract: Recent high-throughput transcript discoveries have yielded a growing recognition of long intergenic non-coding RNAs (lincRNAs), a class of arbitrarily defined transcripts (>200 nt) that are primarily produced from the intergenic space. LincRNAs have been increasingly acknowledged for their expressional dynamics and likely functional associations with cancers. However, differential gene dosage of lincRNA genes between cancer genomes is less studied. By using the high-density Human Omni5-Quad BeadChips (Illumina), we investigated genomic copy number aberrations in a set of seven tumor-normal paired primary human mammary epithelial cells (HMECs) established from patients with invasive ductal carcinoma. This Beadchip platform includes a total of 2,435,915 SNP loci dispersed at an average interval of ~700 nt throughout the intergenic region of the human genome. We mapped annotated or putative lincRNA genes to a subset of 332,539 SNP loci, which were included in our analysis for lincRNA-associated copy number variations (CNV). We have identified 122 lincRNAs, which were affected by somatic CNV with overlapped aberrations ranging from 0.14% to 100% in length. LincRNA-associated aberrations were detected predominantly with copy number losses and preferential clustering to the ends of chromosomes. Interestingly, lincRNA genes appear to be much less susceptible to CNV in comparison to both protein-coding and intergenic regions (CNV affected segments in percentage: 1.8%, 37.5% and 60.6%, respectively). In summary, our study established a novel approach utilizing high-resolution SNP array to identify lincRNA candidates, which could functionally link to tumorigenesis, and provide new strategies for the diagnosis and treatment of breast cancer.
Published: 2012
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7. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

Author: Christopher A Maxwell, Javier Benítez, Laia Gómez-Baldó, Ana Osorio, Núria Bonifaci, Ricardo Fernández-Ramires, Sylvain V Costes, Elisabet Guinó, Helen Chen, Gareth J R Evans, Pooja Mohan, Isabel Català, Anna Petit, Helena Aguilar, Alberto Villanueva, Alvaro Aytes, Jordi Serra-Musach, Gad Rennert, Flavio Lejbkowicz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Carla B Ripamonti, Bernardo Bonanni, Alessandra Viel, Anna Allavena, Loris Bernard, Paolo Radice, Eitan Friedman, Bella Kaufman, Yael Laitman, Maya Dubrovsky, Roni Milgrom, Anna Jakubowska, Cezary Cybulski, Bohdan Gorski, Katarzyna Jaworska, Katarzyna Durda, Grzegorz Sukiennicki, Jan Lubiński, Yin Yao Shugart, Susan M Domchek, Richard Letrero, Barbara L Weber, Frans B L Hogervorst, Matti A Rookus, J Margriet Collee, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal, HEBON, EMBRACE, Douglas F Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Diana Eccles, Fiona Douglas, Carole Brewer, Heli Nevanlinna, Tuomas Heikkinen, Fergus J Couch, Noralane M Lindor, Xianshu Wang, Andrew K Godwin, Maria A Caligo, Grazia Lombardi, Niklas Loman, Per Karlsson, Hans Ehrencrona, Anna von Wachenfeldt, SWE-BRCA, Rosa Bjork Barkardottir, Ute Hamann, Muhammad U Rashid, Adriana Lasa, Trinidad Caldés, Raquel Andrés, Michael Schmitt, Volker Assmann, Kristen Stevens, Kenneth Offit, João Curado, Hagen Tilgner, Roderic Guigó, Gemma Aiza, Joan Brunet, Joan Castellsagué, Griselda Martrat, Ander Urruticoechea, Ignacio Blanco, Laima Tihomirova, David E Goldgar, Saundra Buys, Esther M John, Alexander Miron, Melissa Southey, Mary B Daly, BCFR, Rita K Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Christian Sutter, Dieter Niederacher, Evgeny Imyamitov, Olga M Sinilnikova, Dominique Stoppa-Lyonne, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine de Pauw, Yves-Jean Bignon, Nancy Uhrhammer, Jean-Philippe Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, GEMO Study Collaborators, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Sue Healey, kConFab, Mary Helen Barcellos-Hoff, Marc Vidal, Stephen B Gruber, Conxi Lázaro, Gabriel Capellá, Lesley McGuffog, Katherine L Nathanson, Antonis C Antoniou, Georgia Chenevix-Trench, Markus C Fleisch, Víctor Moreno, and Miguel Angel Pujana
Subjects: Biology (General), QH301-705.5
Abstract: Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
Published: 2011
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8. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Author: Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Phuong L Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N Weitzel, Judy Garber, Ute Hamann, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, and Kenneth Offit
Subjects: Genetics, QH426-470
Abstract: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (
Published: 2010
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9. Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk.

Author: Yan Ding, Garrett Larson, Guillermo Rivas, Cathryn Lundberg, Louis Geller, Ching Ouyang, Jeffrey Weitzel, John Archambeau, Jerry Slater, Mary B Daly, Al B Benson, John M Kirkwood, Peter J O'Dwyer, Rebecca Sutphen, James A Stewart, David Johnson, Magnus Nordborg, and Theodore G Krontiris
Subjects: Medicine, Science
Abstract: Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's chi(2) = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's chi(2) = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (pi = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (pi = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.
Published: 2008
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10. Defining aggressive prostate cancer: a geospatial perspective

Author: Daniel Wiese, Tesla D. DuBois, Kristen A. Sorice, Carolyn Y. Fang, Camille Ragin, Mary B. Daly, Adam C. Reese, Kevin A. Henry, and Shannon M. Lynch
Subjects: Prostate cancer, Geospatial, Aggressive prostate cancer, Survival analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Spatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets. Methods Using the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign “aggressive” status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression). Results The number of “aggressive” PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging. Conclusions Using D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies.
Published: 2023
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11. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author: Anna Morra, Maartje A. C. Schreurs, Irene L. Andrulis, Hoda Anton‐Culver, Annelie Augustinsson, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Annegien Broeks, Saundra S. Buys, Nicola J. Camp, Jose E. Castelao, Melissa H. Cessna, Jenny Chang‐Claude, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Tanja N. Fehm, Jonine D. Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago‐Dominguez, Montserrat García‐Closas, José A. García‐Sáenz, Jeanine Genkinger, Felix Grassmann, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, ABCTB Investigators, kConFab Investigators, Anna Jakubowska, Wolfgang Janni, Helena Jernström, Esther M. John, Nichola Johnson, Michael E. Jones, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Michael P. Lux, Arto Mannermaa, Dimitrios Mavroudis, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, Ines Nevelsteen, Patrick Neven, William G. Newman, Nadia Obi, Kenneth Offit, Andrew F. Olshan, Tjoung‐Won Park‐Simon, Alpa V. Patel, Paolo Peterlongo, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Eric C. Polley, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Muhammad U. Rashid, Valerie Rhenius, Mark Robson, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Sabine Schuetze, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, William J. Tapper, Lauren R. Teras, Rob A. E. M. Tollenaar, Katarzyna Tomczyk, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Elke M. vanVeen, Qin Wang, Camilla Wendt, Hans Wildiers, Robert Winqvist, Argyrios Ziogas, Per Hall, Paul D. P. Pharoah, Muriel A. Adank, Antoinette Hollestelle, Marjanka K. Schmidt, and Maartje J. Hooning
Subjects: CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
Published: 2023
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12. The association between age at breast cancer diagnosis and prevalence of pathogenic variants

Author: Mary B. Daly, Eric Rosenthal, Shelly Cummings, Ryan Bernhisel, John Kidd, Elisha Hughes, Alexander Gutin, Stephanie Meek, Thomas P. Slavin, and Allison W. Kurian
Subjects: Cancer Research, Oncology
Abstract: Purpose Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2. Methods We analyzed multi-gene panel testing results (09/2013–12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry. Results An association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64–4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84–2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08–1.37) and CHEK2 (OR 1.34, 95% CI 1.21–1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98–1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13–2.56) and BRCA2 (OR 1.25, 95% CI 1.16–1.35). Conclusions Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.
Published: 2023
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13. Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry

Author: Danielle E. Haslam, Esther M. John, Julia A. Knight, Zhongyu Li, Saundra S. Buys, Irene L. Andrulis, Mary B. Daly, Jeanine M. Genkinger, Mary Beth Terry, and Fang Fang Zhang
Subjects: Oncology, Epidemiology
Abstract: Background: The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH). Methods: Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI). Results: Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74–1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69–0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59–0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65–0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index Conclusions: Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer. Impact: Adherence to a healthy diet may improve survival of women with breast cancer.
Published: 2023
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14. Understanding clinical communication about mood disturbance symptoms among breast cancer patients: A mixed methods analysis

Author: Lauren A, Zimmaro, Kristen A, Sorice, Elizabeth A, Handorf, Mary B, Daly, and Jennifer B, Reese
Subjects: Depression, Communication, Quality of Life, Humans, Breast Neoplasms, Female, General Medicine, Anxiety, Middle Aged, Article
Abstract: OBJECTIVES: We aimed to characterize the relationships between breast cancer patient mood symptom severity and demographic/medical factors with clinical communication about mood, and to explore mood discussion content. METHODS: 134 breast cancer patients (mean age=58.3; 14% minority; 13% metastatic) had oncology clinic visits audio-recorded, transcribed, and coded for mood communication. Patient Care Monitor assessed mood symptoms (anxiety/depression presence/severity). Logistic regressions measured associations between mood, demographic/medical factors, and communication. Thematic analysis characterized discussion topics. RESULTS: Over half of patients (55%; n=73) reported mood symptoms. Worse mood symptoms were associated with younger age and current treatment (p’s
Published: 2022
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15. Investigating the impact of the COVID-19 pandemic on breast cancer clinicians’ communication about sexual health

Author: Jennifer Barsky Reese, Areej El-Jawahri, Kristen Sorice, Christina Cruz, Sharon L. Bober, Mary B. Daly, Lauren A. Zimmaro, Mary Catherine Beach, Elaine Wittenberg, Antonio C. Wolff, Elizabeth Handorf, and Stephen J. Lepore
Subjects: Oncology
Published: 2022
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16. Table S2 from Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry

Author: Fang Fang Zhang, Mary Beth Terry, Jeanine M. Genkinger, Mary B. Daly, Irene L. Andrulis, Saundra S. Buys, Zhongyu Li, Julia A. Knight, Esther M. John, and Danielle E. Haslam
Abstract: Table S2 Shows Pearson's Correlation Coefficients (r) for Diet Quality Index Scores
Published: 2023
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17. Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing

Author: Elena V. Demidova, Ilya G. Serebriiskii, Ramilia Vlasenkova, Simon Kelow, Mark D. Andrake, Tiffiney R. Hartman, Tatiana Kent, James Virtucio, Gail L. Rosen, Richard T. Pomerantz, Roland L. Dunbrack, Erica A. Golemis, Michael J. Hall, David Y. T. Chen, Mary B. Daly, and Sanjeevani Arora
Subjects: Genetics, Biotechnology
Abstract: Background Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Methods Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. Results Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of $$\gamma$$ γ H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased $$\gamma$$ γ H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Conclusions Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.
Published: 2023
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18. Data from Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry

Author: Fang Fang Zhang, Mary Beth Terry, Jeanine M. Genkinger, Mary B. Daly, Irene L. Andrulis, Saundra S. Buys, Zhongyu Li, Julia A. Knight, Esther M. John, and Danielle E. Haslam
Abstract: Background:The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH).Methods:Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI).Results:Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74–1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69–0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59–0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65–0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index 2 and women with hormone receptor positive tumors.Conclusions:Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer.Impact:Adherence to a healthy diet may improve survival of women with breast cancer.
Published: 2023
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19. Data from Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)

Author: John L. Hopper, Mary Beth Terry, Graham G. Giles, Melissa C. Southey, Pierre-Antoine Dugué, Roger L. Milne, Ingrid M. Winship, Heather Thorne, Kelly-Anne Phillips, Wendy K. Chung, Jeanine M. Genkinger, Allison W. Kurian, Esther M. John, Mary B. Daly, Saundra S. Buys, Irene L. Andrulis, Robert J. MacInnis, Tuong L. Nguyen, Gillian S. Dite, Shuai Li, and Zhoufeng Ye
Abstract: We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk.Prevention Relevance:Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum.
Published: 2023
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20. Supplementary Data from Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)

Author: John L. Hopper, Mary Beth Terry, Graham G. Giles, Melissa C. Southey, Pierre-Antoine Dugué, Roger L. Milne, Ingrid M. Winship, Heather Thorne, Kelly-Anne Phillips, Wendy K. Chung, Jeanine M. Genkinger, Allison W. Kurian, Esther M. John, Mary B. Daly, Saundra S. Buys, Irene L. Andrulis, Robert J. MacInnis, Tuong L. Nguyen, Gillian S. Dite, Shuai Li, and Zhoufeng Ye
Abstract: Supplementary Data from Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)
Published: 2023
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21. Table S7 from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author: Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu
Abstract: Variants with P < 5E-8 either in BCAC or OCAC between 42,836,399 and 44,910,520 on the chromosome 17.
Published: 2023
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22. Data from Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk – Combined Results from Two Screening Trials

Author: Karen H. Lu, Dianne M. Finkelstein, David Alberts, Susan Nayfield, Carol H. Kasten, Nora K. Horick, Lori Minasian, William Welch, Patrick M. Sluss, Joan Walker, Carol J. Fabian, Ira Horowitz, Deborah Armstrong, Kelly-Anne Phillips, Katie Wakeley, Steven A. Elg, Robert Edwards, Susan A. Davidson, Susan Domchek, Andrew Berchuck, Claudine Isaacs, Charles W. Drescher, John Boggess, Edward Partridge, David M. O'Malley, Wendy R. Brewster, Thomas Rutherford, Mary B. Daly, Mark Sherman, John O. Schorge, Gustavo Rodriguez, Marion Piedmonte, Powel Brown, Phuong L. Mai, Saundra S. Buys, Mark H. Greene, and Steven J. Skates
Abstract: Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628–37. ©2017 AACR.
Published: 2023
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23. Supplementary Figure S2 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author: Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang
Abstract: Genetic analyses of BRCA1 mutant cell lines and PDX models.
Published: 2023
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24. Supplementary Data from Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk

Author: Mary Beth Terry, John L. Hopper, Mary B. Daly, Saundra S. Buys, Irene L. Andrulis, kConFab Investigators, Stephanie Nesci, Gord Glendon, Prue C. Weideman, Michael Friedlander, Kristen D. Whitaker, Sue-Anne McLachlan, Graham G. Giles, Wendy K. Chung, Melissa C. Southey, Julia A. Knight, Yuyan Liao, Nur Zeinomar, Roger L. Milne, Gillian S. Dite, Kelly-Anne Phillips, Esther M. John, Robert J. MacInnis, Jeanine M. Genkinger, and Rebecca D. Kehm
Abstract: e Table1 contains the minimum number of average metabolic equivalents (METs) per week required to be classified as physically active at baseline and in adolescence for a given age at baseline. eTable 2 presents the association of baseline and adolescent strenuous and moderate recreational physical activity with breast cancer risk in the Prospective Family Study Cohort (N=15,500).
Published: 2023
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25. Supplementary Tables 1-4 from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: PDF file - 90K
Published: 2023
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26. Data from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author: Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang
Abstract: Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778–90. ©2016 AACR.
Published: 2023
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27. Supplementary Figure Legends from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author: Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang
Abstract: Legend for Supplementary Figures S1-S6.
Published: 2023
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28. Supplementary Tables S1-S4 from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author: Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang
Abstract: RNA-seq analyses of global exon splicing events (S1); Cell line therapy sensitivities (S2); Hazard ratios for survival of patients with serous ovarian carcinomas associated with BRCA1 mutation, age at diagnosis and stage (S3); Characteristics of studies included in survival analysis from Fig. 5A (S4).
Published: 2023
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29. Data from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.
Published: 2023
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30. Online Supplementary Materials from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author: Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu
Abstract: Online Supplementary Documents
Published: 2023
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31. Data from A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Author: Jirong Long, Wei Zheng, Paul D.P. Pharoah, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Andrew Berchuck, Antonis C. Antoniou, Simon A. Gayther, Kristin K. Zorn, Drakoulis Yannoukakos, Anna H. Wu, Alicja Wolk, Emily White, Nicolas Wentzensen, Jeffrey N. Weitzel, Penelope M. Webb, Digna Velez Edwards, Ana Vega, Adriaan Vanderstichele, Elizabeth J. van Rensburg, Shelley S. Tworoger, Nadine Tung, Antonia Trichopoulou, Amanda E. Toland, Marc Tischkowitz, Mads Thomassen, Soo H. Teo, Manuel R. Teixeira, Anthony J. Swerdlow, Rebecca Sutphen, Amanda B. Spurdle, Melissa C. Southey, Honglin Song, Christian F. Singer, Jacques Simard, Weiva Sieh, Priyanka Sharma, Veronica W. Setiawan, Rita K. Schmutzler, Dale P. Sandler, Iwona K. Rzepecka, Mary Anne Rossing, Matti A. Rookus, Isabelle Romieu, Cristina Rodríguez-Antona, Gustavo C. Rodriguez, Harvey Risch, Gad Rennert, Susan J. Ramus, Miquel Angel Pujana, Catherine M. Phelan, Paolo Peterlongo, Tanja Pejovic, Petra H.M. Peeters, Michael T. Parsons, Sue K. Park, Ana Osorio, Håkan Olsson, Sara H. Olson, Olufunmilayo I. Olopade, Edith Olah, Kenneth Offit, Robert L. Nussbaum, Liene Nikitina-Zake, Finn C. Nielsen, Heli Nevanlinna, Susan L. Neuhausen, Marco Montagna, Francesmary Modugno, Melissa A. Merritt, Iain A. McNeish, Lesley McGuffog, Taymaa May, Amalia Mattiello, Douglas A. Levine, Fabienne Lesueur, Goska Leslie, Nhu D. Le, Ava Kwong, Susanne K. Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Beth Y. Karlan, Paul James, Anna Jakubowska, Claudine Isaacs, Evgeny N. Imyanitov, David G. Huntsman, Peter J. Hulick, Antoinette Hollestelle, Claus K. Høgdall, Michelle A.T. Hildebrandt, Florian Heitz, Ute Hamann, Jacek Gronwald, Mark H. Greene, Marc T. Goodman, David E. Goldgar, Andrew K. Godwin, Graham G. Giles, Judy Garber, Patricia A. Ganz, Eitan Friedman, George Fountzilas, Renée T. Fortner, Peter A. Fasching, Diana M. Eccles, Douglas F. Easton, Thilo Dörk, Susan M. Domchek, Orland Diez, Joe Dennis, Anna deFazio, Mary B. Daly, Daniel W. Cramer, Fergus J. Couch, Kathleen B.M. Claes, Jenny Chang-Claude, Ian Campbell, Maria A. Caligo, Trinidad Caldes, Ralf Butzow, James Brenton, Line Bjorge, Javier Benitez, Daniel R. Barnes, Rosa B. Barkardottir, Elisa V. Bandera, Banu K. Arun, Hoda Anton-Culver, Irene L. Andrulis, Kirsten B. Moysich, Jamie K. Teer, Brett M. Reid, Jennifer B. Permuth, Yian A. Chen, Hae Kyung Im, Joellen M. Schildkraut, Bingshan Li, Xingyi Guo, Lang Wu, Alicia Beeghly-Fadiel, and Yingchang Lu
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
Published: 2023
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32. Supplementary Table 1 from Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers

Author: Daniel L. Gillen, Joanne L. Blum, Nadine Tung, Wendy S. Rubinstein, Gail E. Tomlinson, Olufunmilayo I. Olopade, Claudine Isaacs, Mary B. Daly, Patricia A. Ganz, Steven A. Narod, Andrew Godwin, Jeffrey N. Weitzel, Fergus Couch, Judy E. Garber, Henry T. Lynch, Georg Pfeiler, Christian F. Singer, Timothy R. Rebbeck, Susan Domchek, Katherine L. Nathanson, Linda Steele, Yuan Chun Ding, Sean Brummel, and Susan L. Neuhausen
Abstract: Supplementary Table 1 from Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers
Published: 2023
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33. Data from Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk

Author: Mary Beth Terry, John L. Hopper, Mary B. Daly, Saundra S. Buys, Irene L. Andrulis, kConFab Investigators, Stephanie Nesci, Gord Glendon, Prue C. Weideman, Michael Friedlander, Kristen D. Whitaker, Sue-Anne McLachlan, Graham G. Giles, Wendy K. Chung, Melissa C. Southey, Julia A. Knight, Yuyan Liao, Nur Zeinomar, Roger L. Milne, Gillian S. Dite, Kelly-Anne Phillips, Esther M. John, Robert J. MacInnis, Jeanine M. Genkinger, and Rebecca D. Kehm
Abstract: Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history (N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68–0.93). The association was not modified by familial risk or BRCA mutation status (P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk.Significance:These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility.See related commentary by Niehoff et al., p. 23
Published: 2023
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34. Supplementary Materials from Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk – Combined Results from Two Screening Trials

Author: Karen H. Lu, Dianne M. Finkelstein, David Alberts, Susan Nayfield, Carol H. Kasten, Nora K. Horick, Lori Minasian, William Welch, Patrick M. Sluss, Joan Walker, Carol J. Fabian, Ira Horowitz, Deborah Armstrong, Kelly-Anne Phillips, Katie Wakeley, Steven A. Elg, Robert Edwards, Susan A. Davidson, Susan Domchek, Andrew Berchuck, Claudine Isaacs, Charles W. Drescher, John Boggess, Edward Partridge, David M. O'Malley, Wendy R. Brewster, Thomas Rutherford, Mary B. Daly, Mark Sherman, John O. Schorge, Gustavo Rodriguez, Marion Piedmonte, Powel Brown, Phuong L. Mai, Saundra S. Buys, Mark H. Greene, and Steven J. Skates
Abstract: Supplementary Materials describing "Inclusion and Exclusion Criteria" for the two studies, a detailed description of the "ROCA methods", "Sample Handling and CA125 Assay Instrumentation", and derivation of standards for "Specificity and Positive Predictive Values" for a cohort of women at increased risk.
Published: 2023
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35. Data from Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers

Author: Daniel L. Gillen, Joanne L. Blum, Nadine Tung, Wendy S. Rubinstein, Gail E. Tomlinson, Olufunmilayo I. Olopade, Claudine Isaacs, Mary B. Daly, Patricia A. Ganz, Steven A. Narod, Andrew Godwin, Jeffrey N. Weitzel, Fergus Couch, Judy E. Garber, Henry T. Lynch, Georg Pfeiler, Christian F. Singer, Timothy R. Rebbeck, Susan Domchek, Katherine L. Nathanson, Linda Steele, Yuan Chun Ding, Sean Brummel, and Susan L. Neuhausen
Abstract: Background:BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.
Published: 2023
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36. Supplementary Methods and References from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

Author: Neil Johnson, Violeta Serra, Judith Balmaña, Jos Jonkers, Peter Bouwman, Elizabeth M. Swisher, Mary B. Daly, Denise C. Connolly, David L. Wiest, Geoffrey I. Shapiro, Alan D. D'Andrea, Susanne K. Kjaer, Simon A. Gayther, Siegal Sadetzki, Robert Nussbaum, Martin Gore, Mark H. Greene, Javier J. Benitez, Håkan Olsson, Georgia Chenevix-Trench, Diether Lambrechts, Charlie Gourley, Beth Karlan, Paul D. P. Pharoah, Francisco J. Candido Dos Reis, Shawn F. Johnson, Maribel I. Harrell, Yong Zhang, Shane W. O'Brien, Ingrid van der Heijden, Hanneke van der Gulden, Suraj Peri, Emmanuelle Nicolas, Joseph Nacson, John J. Krais, Cristina Cruz, Andrea J. Bernhardy, and Yifan Wang
Abstract: Description of additional methods and procedures used in the study. Also includes Supplementary References.
Published: 2023
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37. Supplementary Methods, Tables 1-3, Figure 1 from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis

Author: Garrett P. Larson, David Johnson, James A. Stewart, Rebecca Sutphen, Peter J. O'Dwyer, John M. Kirkwood, Al B. Benson, Mary B. Daly, Jeffrey Weitzel, Theodore G. Krontiris, John J. Rossi, Jessica Alluin, Guillermo E. Rivas, Karim Majzoub, Laurent F. Thomas, David Smith, Sierra M. Li, Jacob Biesinger, and Pål Sætrom
Abstract: Supplementary Methods, Tables 1-3, Figure 1 from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis
Published: 2023
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38. Supplementary Figure and Table Legends from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis

Author: Garrett P. Larson, David Johnson, James A. Stewart, Rebecca Sutphen, Peter J. O'Dwyer, John M. Kirkwood, Al B. Benson, Mary B. Daly, Jeffrey Weitzel, Theodore G. Krontiris, John J. Rossi, Jessica Alluin, Guillermo E. Rivas, Karim Majzoub, Laurent F. Thomas, David Smith, Sierra M. Li, Jacob Biesinger, and Pål Sætrom
Abstract: Supplementary Figure and Table Legends from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis
Published: 2023
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39. Data from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]
Published: 2023
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40. Data from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis

Author: Garrett P. Larson, David Johnson, James A. Stewart, Rebecca Sutphen, Peter J. O'Dwyer, John M. Kirkwood, Al B. Benson, Mary B. Daly, Jeffrey Weitzel, Theodore G. Krontiris, John J. Rossi, Jessica Alluin, Guillermo E. Rivas, Karim Majzoub, Laurent F. Thomas, David Smith, Sierra M. Li, Jacob Biesinger, and Pål Sætrom
Abstract: MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor–stratified breast tumors and used local linkage disequilibirum patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong linkage disequilibrium with rs1434536, an SNP that resides within a miR-125b target site in the 3′ untranslated region of the bone morphogenic receptor type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture-corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b–mimics combined with quantitative reverse transcription-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease association for alleles that affect miRNA regulation. [Cancer Res 2009;69(18):7459–65]
Published: 2023
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41. Supplementary Table 2: Revised 7-14-09 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Supplementary Table 2: Revised 7-14-09 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Published: 2023
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42. Supplementary Table 4 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Supplementary Table 4 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Published: 2023
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43. Supplementary Figure from Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT

Author: Theodore G. Krontiris, Robert C. Elston, John C. Ruckdeschel, David Johnson, Jae Werndli, James A. Stewart, Rosalind Drew, Rebecca Sutphen, Barbara Raskay, Peter J. O'Dwyer, John M. Kirkwood, Kimberly Smith, Al B. Benson, Irene Angel, Mary B. Daly, Donna Neuberg, Jerry Slater, John Archambeau, Deborah MacDonald, Jeffrey Weitzel, Louis Geller, Guillermo Rivas, Virgil Gagalang, Cathryn Lundberg, Li S-C. Cheng, Yan Ding, and Garry P. Larson
Abstract: Supplementary Figure from Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT
Published: 2023
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44. Supplementary Table 3 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Supplementary Table 3 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Published: 2023
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45. Data from Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT

Author: Theodore G. Krontiris, Robert C. Elston, John C. Ruckdeschel, David Johnson, Jae Werndli, James A. Stewart, Rosalind Drew, Rebecca Sutphen, Barbara Raskay, Peter J. O'Dwyer, John M. Kirkwood, Kimberly Smith, Al B. Benson, Irene Angel, Mary B. Daly, Donna Neuberg, Jerry Slater, John Archambeau, Deborah MacDonald, Jeffrey Weitzel, Louis Geller, Guillermo Rivas, Virgil Gagalang, Cathryn Lundberg, Li S-C. Cheng, Yan Ding, and Garry P. Larson
Abstract: We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's χ2 = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.
Published: 2023
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46. Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Author: Douglas F. Easton, Georgia Chenevix-Trench, Radka Platte, Xiaoqing Chen, Helene Holland, Amanda B. Spurdle, Jacques Simard, Heli Nevanlinna, Kristiina Aittomäki, Miguel de la Hoya, Trinidad Caldes, Ines Schönbuchner, Karin Kast, Sabine Preisler-Adams, Dorothea Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Raymonda Varon-Mateeva, Simone Heidemann, Norbert Arnold, Magdalena Lochmann, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita Schmutzler, Jenny Gross, Beth Y. Karlan, Lara Sucheston, Susan J. Ramus, Conxi Lazaro, Ignacio Blanco, Laima Tihomirova, Evgeny Imyanitov, Cinzia Casella, Marco Montagna, Amanda Ewart Toland, Stephanie V. Blank, Peter E. Schwartz, Jack Basil, John F. Boggess, Katie Wakeley, Gustavo C. Rodriguez, Marion Piedmonte, Ana Dutra-Clarke, Vincent Devlin, Kenneth Offit, Tomas Kirchhoff, Bjarni A. Agnarsson, Lars Jønson, Thomas V.O. Hansen, Georg Pfeiler, Daphne Gschwantler-Kaulich, Anne Catharina Dressler, Christian F. Singer, David Goldgar, Alexander Miron, Yosuf Yassin, Saundra S. Buys, Esther M. John, Mary B. Terry, Mary B. Daly, John L. Hopper, Laurence Vénat-Bouvet, Marc Frénay, Catherine Nogues, Etienne Rouleau, Hagay Sobol, Tetsuro Noguchi, Catherine Loustalot, Laurence Faivre, Pascaline Berthet, Agnès Hardouin, Dominique Leroux, Hélène Dreyfus, Christine Lasset, Valérie Bonadona, Sylvie Mazoyer, Antoine de Pauw, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Susan Peock, Huw Dorkins, M. John Kennedy, Lisa Walker, Mary E. Porteous, Patrick J. Morrison, Shirley Hodgson, Joan Paterson, Jackie Cook, Trevor Cole, Rosemarie Davidson, Gabriella Pichert, Fiona Lalloo, D. Gareth Evans, Don Conroy, Debra Frost, Clare Oliver, Margaret Cook, Matti Rookus, Frans Hogervorst, Cora M. Aalfs, Marinus J. Blok, E.J. Meijers-Heijboer, Peter Devilee, Christi J. van Asperen, Rob B. van der Luijt, Nicoline Hoogerbrugge, Mieke Kriege, Ute Hamann, Javier Benitez, Javier Godino, Maria-Isabel Tejada, Mercedes Durán, Adriana Lasa, Ana Osorio, Tomasz Huzarski, Jan Lubinski, Ania Jakubowska, Susan Domchek, Kate Nathanson, Beatrice Melin, Marie Stenmark-Askmalm, Johanna Rantala, Annika Lindblom, Helena Jernström, Ake Borg, Shimrit Cohen, Maya Dubrovsky, Roni Milgrom, Yael Laitman, Bella Kaufman, Eitan Friedman, Maria Caligo, Uffe Birk Jensen, Dorthe Cruger, Lone Sunde, Anne-Marie Gerdes, Mads Thomassen, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Flavio Lejbkowicz, Gad Rennert, Mark H. Greene, Phuong L. Mai, Lenka Foretova, Bruce Poppe, Kathleen Claes, Michal Zikan, Csilla I. Szabo, Paolo Peterlongo, Valentina Dall'Olio, Anna Allavena, Alessandra Viel, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Vernon S. Pankratz, Noralane M. Lindor, Xianshu Wang, Fergus J. Couch, Olufunmilayo I. Olopade, Gail Tomlinson, Patricia A. Ganz, Claudine Isaacs, Henry T. Lynch, Jeffrey N. Weitzel, Timothy R. Rebbeck, Yuan Chun Ding, Susan L. Neuhausen, Sue Healey, Olga M. Sinilnikova, Lesley McGuffog, Jonathan Beesley, and Antonis C. Antoniou
Abstract: Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
Published: 2023
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47. Supplementary Table 2 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Supplementary Table 2 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Published: 2023
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48. Supplementary Table 1 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Author: Mary B. Daly, Katherine L. Nathanson, Roger Greenberg, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Patricia A. Ganz, Gail E. Tomlinson, Wendy S. Rubinstein, Steven A. Narod, Fergus Couch, Claudine Isaacs, Jeffrey N. Weitzel, Judy E. Garber, Henry T. Lynch, Susan L. Neuhausen, Georg Pfeiler, Christian F. Singer, Georgia Chenevix-Trench, Amanda Spurdle, Saarene Panossian, Tara M. Friebel, Shannon Chuai, Fei Wan, Susan M. Domchek, Nandita Mitra, and Timothy R. Rebbeck
Abstract: Supplementary Table 1 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Published: 2023
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49. Cascade Genetic Testing for Hereditary Cancer Risk: An Underutilized Tool for Cancer Prevention

Author: Mary B. Daly, Elias Obeid, Michael J. Hall, and Kristen Danielle Whitaker
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Cancer prevention, medicine.diagnostic_test, business.industry, Risk Assessment, Neoplasms, Internal medicine, medicine, Humans, Hereditary Cancer, Genetic Testing, business, Genetic testing
Published: 2021
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50. Multigene assessment of genetic risk for women for two or more breast cancers

Author: Thomas P. Slavin, Anna Gardiner, Elisha Hughes, Paul Frankel, Krystal Brown, Jennifer Saam, Diana Turco, Kathleen R. Blazer, Shelly Cummings, Bita Nehoray, Ryan Bernhisel, Jeffrey N. Weitzel, Kim McGreevy, Susan Shehayeb, Kira Svirsky, Mary B. Daly, and John Kidd
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Family Cancer History, PALB2, Genes, BRCA2, Breast Neoplasms, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, PTEN, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, CHEK2, Germ-Line Mutation, biology, business.industry, Odds ratio, medicine.disease, Penetrance, MSH6, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, business
Abstract: PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013–2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53–1.79, p=7.2 × 10(−33)) and synchronous (OR 1.33, 95% CI 1.19–1.50, p=2.4 × 10(−6)) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.
Published: 2021
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