Author: "Jacques Simard" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Jacques Simard"' showing total 486 results

Start Over Author "Jacques Simard"

486 results on '"Jacques Simard"'

1. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Karin Kast, Esther M. John, John L. Hopper, Nadine Andrieu, Catherine Noguès, Emmanuelle Mouret-Fourme, Christine Lasset, Jean-Pierre Fricker, Pascaline Berthet, Véronique Mari, Lucie Salle, Marjanka K. Schmidt, Margreet G. E. M. Ausems, Encarnacion B. Gomez Garcia, Irma van de Beek, Marijke R. Wevers, D. Gareth Evans, Marc Tischkowitz, Fiona Lalloo, Jackie Cook, Louise Izatt, Vishakha Tripathi, Katie Snape, Hannah Musgrave, Saba Sharif, Jennie Murray, EMBRACE Collaborators, Sarah V. Colonna, Irene L. Andrulis, Mary B. Daly, Melissa C. Southey, Miguel de la Hoya, Ana Osorio, Lenka Foretova, Dita Berkova, Anne-Marie Gerdes, Edith Olah, Anna Jakubowska, Christian F. Singer, Yen Tan, Annelie Augustinsson, Johanna Rantala, Jacques Simard, Rita K. Schmutzler, Roger L. Milne, Kelly-Anne Phillips, Mary Beth Terry, David Goldgar, Flora E. van Leeuwen, Thea M. Mooij, Antonis C. Antoniou, Douglas F. Easton, Matti A. Rookus, and Christoph Engel
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Introduction Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. Patients and methods An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. Results In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66–0.84) and BRCA2 (HR 0.76, 95% CI 0.65–0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02–1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01–1.19, respectively). Conclusion Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Published: 2023
Full Text: View/download PDF

2. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author: Stefanie H. Mueller, Alvina G. Lai, Maria Valkovskaya, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Zomoruda Abu-Ful, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Thais Baert, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Sara Y. Brucker, Saundra S. Buys, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Ji-Yeob Choi, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, CTS Consortium, Sten Cornelissen, Fergus J. Couch, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Manuela Gago-Dominguez, Yu-Tang Gao, Montserrat García-Closas, José A. García-Sáenz, Jeanine Genkinger, Aleksandra Gentry-Maharaj, Felix Grassmann, Pascal Guénel, Melanie Gündert, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Elaine F. Harkness, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Weang-Kee Ho, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Dezheng Huo, ABCTB Investigators, Hidemi Ito, Motoki Iwasaki, Anna Jakubowska, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Daehee Kang, Elza K. Khusnutdinova, Sung-Won Kim, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Martha Linet, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Usha Menon, Kenneth Muir, Rachel A. Murphy, Heli Nevanlinna, William G. Newman, Dieter Niederacher, Katie M. O’Brien, Nadia Obi, Kenneth Offit, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Sue K. Park, Alpa V. Patel, Achal Patel, Charles M. Perou, Julian Peto, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Michael O. Schneider, Christopher Scott, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Jacques Simard, Harald Surowy, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Amanda E. Toland, Rob A. E. M. Tollenaar, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Robert Winqvist, Alicja Wolk, Anna H. Wu, Taiki Yamaji, Xiaohong R. Yang, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Douglas F. Easton, Harry Hemingway, Ute Hamann, and Karoline B. Kuchenbaecker
Subjects: Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, Medicine, Genetics, QH426-470
Abstract: Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q
Published: 2023
Full Text: View/download PDF

3. Using Real-World Data to Determine Health System Costs of Ontario Women Screened for Breast Cancer

Author: Nicole Mittmann, Soo Jin Seung, Christina Diong, Jodi M. Gatley, Michael Wolfson, Marie-Hélène Guertin, Nora Pashayan, Jacques Simard, and Anna M. Chiarelli
Subjects: breast cancer screening, costs, mammograms, diagnostics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Our study was to determine breast cancer screening costs in Ontario, Canada for screenings conducted through a formal (Ontario Breast Screening Program, OBSP) and informal (non-OBSP) screening program using administrative databases. Included women were 49–74 years of age when receiving screening mammograms between 1 January 2013 to 31 December 2019. Each woman was followed for a screening episode with screening and diagnostic components, and costs were calculated as an average cost per woman per month in 2021 Canadian dollars. The final cohort of 1,546,386 women screened had a mean age of 59.4 ± 7.1 years and ~87% were screened via OBSP. The average total cost per woman per month was $136 ± $103, $134 ± $103 and $155 ± $104 for the entire, OBSP and non-OBSP cohorts, respectively. This was further disaggregated into the average total screening cost per month, which was $103 ± $8, $100 ± $4 and $117 ± $9 per woman, and the average total diagnostic cost per woman per month at $219 ± $166, $228 ± $165 and $178 ± $159. for the entire, OBSP and non-OBSP cohorts, respectively. These results indicate similar screening costs across the different cohorts, but higher diagnostic costs for the OBSP cohort.
Published: 2022
Full Text: View/download PDF

4. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A. R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami Belhadj, Lieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, GEMO Study Collaborators, EMBRACE Collaborators, Marie-Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman, Megan Frone, Debra Frost, Judy Garber, Simon A. Gayther, Andrea Gehrig, Paul Gesta, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Eric Hahnen, Christopher R. Hake, Ute Hamann, Thomas V. O. Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J. Hulick, Evgeny N. Imyanitov, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, John W. M. Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C. Rodriguez, Karina Rønlund, Efraim H. Rosenberg, Maria Rossing, Rita K. Schmutzler, Payal D. Shah, Saba Sharif, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Alison H. Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N. Weitzel, Marike R. Wevers, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, and Logan C. Walker
Subjects: Biology (General), QH301-705.5
Abstract: The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.
Published: 2022
Full Text: View/download PDF

5. Gynecologic Cancer Risk and Genetics: Informing an Ideal Model of Gynecologic Cancer Prevention

Author: Lauren C. Tindale, Almira Zhantuyakova, Stephanie Lam, Michelle Woo, Janice S. Kwon, Gillian E. Hanley, Bartha Knoppers, Kasmintan A. Schrader, Stuart J. Peacock, Aline Talhouk, Trevor Dummer, Kelly Metcalfe, Nora Pashayan, William D. Foulkes, Ranjit Manchanda, David Huntsman, Gavin Stuart, Jacques Simard, and Lesa Dawson
Subjects: cancer screening, hereditary cancer syndrome, population-based genetic testing, BRCA, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit “Gynecologic Cancer Prevention: Thinking Big, Thinking Differently” in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy.
Published: 2022
Full Text: View/download PDF

6. Women’s perceptions of PERSPECTIVE: a breast cancer risk stratification e-platform

Author: Saima Ahmed, Emmanuelle Lévesque, Rosalind Garland, Bartha Knoppers, Michel Dorval, Jacques Simard, and Carmen G. Loiselle
Subjects: Breast cancer, cancer risk stratification, cancer prevention and screening, e-health, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Abstract: Abstract Background Breast cancer risk stratification categorizes a woman’s potential risk of developing the disease as near-population, intermediate, or high. In accordance, screening and follow up for breast cancer can readily be tailored following risk assessment. Recent efforts have focussed on developing more accessible means to convey this information to women. This study sought to document the relevance of an informational e-platform developed for these purposes. Objective To begin to assess a newly developed breast cancer risk stratification and decision support e-platform called PERSPECTIVE (PErsonalised Risk Stratification for Prevention and Early deteCTIon of breast cancer) among women who do not know their personal breast cancer risk (Phase 1). Changes (pre- and post- e-platform exposure) in knowledge of breast cancer risk and interest in undergoing genetic testing were assessed in addition to perceptions of platform usability and acceptability. Methods Using a pre-post design, women (N = 156) of differing literacy and education levels, aged 30 to 60, with no previous breast cancer diagnosis were recruited from the general population and completed self-report e-questionnaires. Results Mean e-platform viewing time was 18.67 min (SD 0.65) with the most frequently visited pages being breast cancer-related risk factors and risk assessment. Post-exposure, participants reported significantly higher breast cancer-related knowledge (p
Published: 2022
Full Text: View/download PDF

7. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Thomas U. Ahearn, Haoyu Zhang, Kyriaki Michailidou, Roger L. Milne, Manjeet K. Bolla, Joe Dennis, Alison M. Dunning, Michael Lush, Qin Wang, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Adinda Baten, Heiko Becher, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Diana M. Eccles, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Giuseppe Floris, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mark S. Goldberg, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Bernadette A. M. Heemskerk-Gerritsen, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Milena Jakimovska, Anna Jakubowska, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Saila Kauppila, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Katerina Kubelka-Sabit, Allison W. Kurian, Kyriacos Kyriacou, Diether Lambrechts, Derrick G. Lee, Annika Lindblom, Martha Linet, Jolanta Lissowska, Ana Llaneza, Wing-Yee Lo, Robert J. MacInnis, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Maria Elena Martinez, Catriona McLean, Alfons Meindl, Usha Menon, Heli Nevanlinna, William G. Newman, Jesse Nodora, Kenneth Offit, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Julian Peto, Guillermo Pita, Dijana Plaseska-Karanfilska, Ross Prentice, Kevin Punie, Katri Pylkäs, Paolo Radice, Gad Rennert, Atocha Romero, Thomas Rüdiger, Emmanouil Saloustros, Sarah Sampson, Dale P. Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Ben Schöttker, Mark E. Sherman, Xiao-Ou Shu, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Diana Torres, Melissa A. Troester, Celine M. Vachon, Carolien H. M. van Deurzen, Elke M. van Veen, Philippe Wagner, Clarice R. Weinberg, Camilla Wendt, Jelle Wesseling, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Fergus J. Couch, Jacques Simard, Peter Kraft, Douglas F. Easton, Paul D. P. Pharoah, Marjanka K. Schmidt, Montserrat García-Closas, and Nilanjan Chatterjee
Subjects: Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate
Published: 2022
Full Text: View/download PDF

8. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Joe Dennis, Jonathan P. Tyrer, Logan C. Walker, Kyriaki Michailidou, Leila Dorling, Manjeet K. Bolla, Qin Wang, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Jose E. Castelao, Jenny Chang-Claude, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, CTS Consortium, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Laure Dossus, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Graham G. Giles, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Per Hall, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Agnes Jager, Anna Jakubowska, Esther M. John, Nichola Johnson, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Martha Linet, Alicja Ogrodniczak, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Taru A. Muranen, Rachel A. Murphy, Heli Nevanlinna, Janet E. Olson, Håkan Olsson, Tjoung-Won Park-Simon, Charles M. Perou, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Katri Pylkäs, Gad Rennert, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Rana Shibli, Ann Smeets, Penny Soucy, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Camilla Wendt, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Argyrios Ziogas, Jacques Simard, Alison M. Dunning, Paul D. P. Pharoah, and Douglas F. Easton
Subjects: Biology (General), QH301-705.5
Abstract: Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.
Published: 2022
Full Text: View/download PDF

9. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Author: Na Li, Magnus Zethoven, Simone McInerny, Lisa Devereux, Yu-Kuan Huang, Niko Thio, Dane Cheasley, Sara Gutiérrez-Enríquez, Alejandro Moles-Fernández, Orland Diez, Tu Nguyen-Dumont, Melissa C. Southey, John L. Hopper, Jacques Simard, Martine Dumont, Penny Soucy, Alfons Meindl, Rita Schmutzler, Marjanka K. Schmidt, Muriel A. Adank, Irene L. Andrulis, Eric Hahnen, Christoph Engel, Fabienne Lesueur, Elodie Girard, Susan L. Neuhausen, Elad Ziv, Jamie Allen, Douglas F. Easton, Rodney J. Scott, Kylie L. Gorringe, Paul A. James, and Ian G. Campbell
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
Published: 2021
Full Text: View/download PDF

10. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021
Full Text: View/download PDF

11. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
Subjects: Science
Abstract: In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
Full Text: View/download PDF

12. European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

Author: Weang-Kee Ho, Min-Min Tan, Nasim Mavaddat, Mei-Chee Tai, Shivaani Mariapun, Jingmei Li, Peh-Joo Ho, Joe Dennis, Jonathan P. Tyrer, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Daehee Kang, Ji-Yeob Choi, Suniza Jamaris, Xiao-Ou Shu, Sook-Yee Yoon, Sue K. Park, Sung-Won Kim, Chen-Yang Shen, Jyh-Cherng Yu, Ern Yu Tan, Patrick Mun Yew Chan, Kenneth Muir, Artitaya Lophatananon, Anna H. Wu, Daniel O. Stram, Keitaro Matsuo, Hidemi Ito, Ching Wan Chan, Joanne Ngeow, Wei Sean Yong, Swee Ho Lim, Geok Hoon Lim, Ava Kwong, Tsun L. Chan, Su Ming Tan, Jaime Seah, Esther M. John, Allison W. Kurian, Woon-Puay Koh, Chiea Chuen Khor, Motoki Iwasaki, Taiki Yamaji, Kiak Mien Veronique Tan, Kiat Tee Benita Tan, John J. Spinelli, Kristan J. Aronson, Siti Norhidayu Hasan, Kartini Rahmat, Anushya Vijayananthan, Xueling Sim, Paul D. P. Pharoah, Wei Zheng, Alison M. Dunning, Jacques Simard, Rob Martinus van Dam, Cheng-Har Yip, Nur Aishah Mohd Taib, Mikael Hartman, Douglas F. Easton, Soo-Hwang Teo, and Antonis C. Antoniou
Subjects: Science
Abstract: Polygenic risk scores predict the likelihood that an individual will develop a certain cancer, however these are often specific for a given population. Here, the authors show that a risk score developed to assess the risk of breast cancer in European women can also predict risk in Asian populations.
Published: 2020
Full Text: View/download PDF

13. Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Author: Xiang Shu, Jirong Long, Qiuyin Cai, Sun-Seog Kweon, Ji-Yeob Choi, Michiaki Kubo, Sue K. Park, Manjeet K. Bolla, Joe Dennis, Qin Wang, Yaohua Yang, Jiajun Shi, Xingyi Guo, Bingshan Li, Ran Tao, Kristan J. Aronson, Kelvin Y. K. Chan, Tsun L. Chan, Yu-Tang Gao, Mikael Hartman, Weang Kee Ho, Hidemi Ito, Motoki Iwasaki, Hiroji Iwata, Esther M. John, Yoshio Kasuga, Ui Soon Khoo, Mi-Kyung Kim, Sun-Young Kong, Allison W. Kurian, Ava Kwong, Eun-Sook Lee, Jingmei Li, Artitaya Lophatananon, Siew-Kee Low, Shivaani Mariapun, Koichi Matsuda, Keitaro Matsuo, Kenneth Muir, Dong-Young Noh, Boyoung Park, Min-Ho Park, Chen-Yang Shen, Min-Ho Shin, John J. Spinelli, Atsushi Takahashi, Chiuchen Tseng, Shoichiro Tsugane, Anna H. Wu, Yong-Bing Xiang, Taiki Yamaji, Ying Zheng, Roger L. Milne, Alison M. Dunning, Paul D. P. Pharoah, Montserrat García-Closas, Soo-Hwang Teo, Xiao-ou Shu, Daehee Kang, Douglas F. Easton, Jacques Simard, and Wei Zheng
Subjects: Science
Abstract: In breast cancer, genome-wide associations studies (GWAS) have highlighted loci associated with disease risk. Here, the authors perform a meta-analysis of GWAS data from Asian populations, discovering 31 potential new risk loci, 10 of which are validated in an independent disease cohort.
Published: 2020
Full Text: View/download PDF

14. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Nasim Mavaddat, Antonis C. Antoniou, Thea M. Mooij, Maartje J. Hooning, Bernadette A. Heemskerk-Gerritsen, GENEPSO, Catherine Noguès, Marion Gauthier-Villars, Olivier Caron, Paul Gesta, Pascal Pujol, Alain Lortholary, EMBRACE, Daniel Barrowdale, Debra Frost, D. Gareth Evans, Louise Izatt, Julian Adlard, Ros Eeles, Carole Brewer, Marc Tischkowitz, Alex Henderson, Jackie Cook, Diana Eccles, HEBON, Klaartje van Engelen, Marian J. E. Mourits, Margreet G. E. M. Ausems, Linetta B. Koppert, John L. Hopper, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Mary B. Daly, Saundra S. Buys, kConFab Investigators, Javier Benitez, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Yen Tan, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Flora E. Van Leeuwen, Brita Arver, Håkan Olsson, Rita K. Schmutzler, Christoph Engel, Karin Kast, Kelly-Anne Phillips, Mary Beth Terry, Roger L. Milne, David E. Goldgar, Matti A. Rookus, Nadine Andrieu, Douglas F. Easton, on behalf of IBCCS, kConFab, and BCFR
Subjects: Breast cancer, BRCA1, BRCA2, Mutation, Risk-reducing salpingo-oophorectomy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. Methods A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. Results There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94–1.61) or BRCA2 (HR = 0.88; 95% CI 0.62–1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40–1.15) and 1.07 (95% CI 0.69–1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26–0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. Conclusion We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
Published: 2020
Full Text: View/download PDF

15. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Maria Escala-Garcia, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Alan Ashworth, Paul L. Auer, Päivi Auvinen, Matthias W. Beckmann, Jonathan Beesley, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Suet-Feung Chin, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Miriam Dwek, Helena M. Earl, Diana M. Eccles, A. Heather Eliassen, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Graham G. Giles, David E. Goldgar, Anna González-Neira, Mervi Grip, Pascal Guénel, Qi Guo, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Patricia A. Harrington, Louise Hiller, Maartje J. Hooning, John L. Hopper, Anthony Howell, Chiun-Sheng Huang, Guanmengqian Huang, David J. Hunter, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Pooja Middha Kapoor, Renske Keeman, Cari M. Kitahara, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Flavio Lejbkowicz, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Tabea Maurer, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Nick Orr, Paolo Peterlongo, Christos Petridis, Ross L. Prentice, Nadege Presneau, Kevin Punie, Dhanya Ramachandran, Gad Rennert, Atocha Romero, Mythily Sachchithananthan, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Jacques Simard, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Heather Thorne, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Clare Turnbull, Celine M. Vachon, Lizet E. van der Kolk, Qin Wang, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Argyrios Ziogas, Paul D. P. Pharoah, Per Hall, Lodewyk F. A. Wessels, Georgia Chenevix-Trench, Gary D. Bader, Thilo Dörk, Douglas F. Easton, Sander Canisius, and Marjanka K. Schmidt
Subjects: Science
Abstract: In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
Published: 2020
Full Text: View/download PDF

16. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Author: Siddhartha P. Kar, Daniel P.C. Considine, Jonathan P. Tyrer, Jasmine T. Plummer, Stephanie Chen, Felipe S. Dezem, Alvaro N. Barbeira, Padma S. Rajagopal, Will T. Rosenow, Fernando Moreno, Clara Bodelon, Jenny Chang-Claude, Georgia Chenevix-Trench, Anna deFazio, Thilo Dörk, Arif B. Ekici, Ailith Ewing, George Fountzilas, Ellen L. Goode, Mikael Hartman, Florian Heitz, Peter Hillemanns, Estrid Høgdall, Claus K. Høgdall, Tomasz Huzarski, Allan Jensen, Beth Y. Karlan, Elza Khusnutdinova, Lambertus A. Kiemeney, Susanne K. Kjaer, Rüdiger Klapdor, Martin Köbel, Jingmei Li, Clemens Liebrich, Taymaa May, Håkan Olsson, Jennifer B. Permuth, Paolo Peterlongo, Paolo Radice, Susan J. Ramus, Marjorie J. Riggan, Harvey A. Risch, Emmanouil Saloustros, Jacques Simard, Lukasz M. Szafron, Linda Titus, Cheryl L. Thompson, Robert A. Vierkant, Stacey J. Winham, Wei Zheng, Jennifer A. Doherty, Andrew Berchuck, Kate Lawrenson, Hae Kyung Im, Ani W. Manichaikul, Paul D.P. Pharoah, Simon A. Gayther, and Joellen M. Schildkraut
Subjects: breast cancer, ovarian cancer, pleiotropy, GWAS, transcriptome-wide association study, Genetics, QH426-470
Abstract: Summary: Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
Published: 2021
Full Text: View/download PDF

17. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Hongjie Chen, Arunabha Majumdar, Lu Wang, Siddhartha Kar, Kevin M. Brown, Helian Feng, Constance Turman, Joe Dennis, Douglas Easton, Kyriaki Michailidou, Jacques Simard, Timothy Bishop, Iona C. Cheng, Jeroen R. Huyghe, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Puya Gharahkhani, Johannes Schumacher, Janusz Jankowski, Ines Gockel, Melissa L. Bondy, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Corina Lesseur, Andy R. Ness, Brenda Diergaarde, Andrew F. Olshan, Christopher I. Amos, David C. Christiani, Maria T. Landi, James D. McKay, Myriam Brossard, Mark M. Iles, Matthew H. Law, Stuart MacGregor, Jonathan Beesley, Michelle R. Jones, Jonathan Tyrer, Stacey J. Winham, Alison P. Klein, Gloria Petersen, Donghui Li, Brian M. Wolpin, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Paul Brennan, Stephen J. Chanock, Valerie Gaborieau, Mark P. Purdue, Paul Pharoah, Rayjean J. Hung, Laufey T. Amundadottir, Peter Kraft, Bogdan Pasaniuc, and Sara Lindström
Subjects: cancer, pleiotropy, fine-mapping, 5p15.33 region, TERT, CLPTM1L, Genetics, QH426-470
Abstract: Summary: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021
Full Text: View/download PDF

18. Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Nasim Mavaddat, Antonis C. Antoniou, Thea M. Mooij, Maartje J. Hooning, Bernadette A. Heemskerk-Gerritsen, GENEPSO, Catherine Noguès, Marion Gauthier-Villars, Olivier Caron, Paul Gesta, Pascal Pujol, Alain Lortholary, EMBRACE, Daniel Barrowdale, Debra Frost, D. Gareth Evans, Louise Izatt, Julian Adlard, Ros Eeles, Carole Brewer, Marc Tischkowitz, Alex Henderson, Jackie Cook, Diana Eccles, HEBON, Klaartje van Engelen, Marian J. E. Mourits, Margreet G. E. M. Ausems, Linetta B. Koppert, John L. Hopper, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Mary B. Daly, Saundra S. Buys, kConFab Investigators, Javier Benitez, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Yen Tan, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Flora E. Van Leeuwen, Brita Arver, Håkan Olsson, Rita K. Schmutzler, Christoph Engel, Karin Kast, Kelly-Anne Phillips, Mary Beth Terry, Roger L. Milne, David E. Goldgar, Matti A. Rookus, Nadine Andrieu, Douglas F. Easton, and on behalf of IBCCS, kConFab and BCFR
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.
Published: 2020
Full Text: View/download PDF

19. Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2

Author: Rick A. C. M. Boonen, Amélie Rodrigue, Chantal Stoepker, Wouter W. Wiegant, Bas Vroling, Milan Sharma, Magdalena B. Rother, Nandi Celosse, Maaike P. G. Vreeswijk, Fergus Couch, Jacques Simard, Peter Devilee, Jean-Yves Masson, and Haico van Attikum
Subjects: Science
Abstract: PALB2 is an established breast cancer risk gene but the pathogenicity of many variants remains uncharacterised. Here, the authors present a cDNA-based system for the functional analysis of PALB2 variants of unknown significance.
Published: 2019
Full Text: View/download PDF

20. Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestryResearch in context

Author: Yaohua Yang, Xiang Shu, Xiao-ou Shu, Manjeet K. Bolla, Sun-Seog Kweon, Qiuyin Cai, Kyriaki Michailidou, Qin Wang, Joe Dennis, Boyoung Park, Keitaro Matsuo, Ava Kwong, Sue Kyung Park, Anna H. Wu, Soo Hwang Teo, Motoki Iwasaki, Ji-Yeob Choi, Jingmei Li, Mikael Hartman, Chen-Yang Shen, Kenneth Muir, Artitaya Lophatananon, Bingshan Li, Wanqing Wen, Yu-Tang Gao, Yong-Bing Xiang, Kristan J. Aronson, John J. Spinell, Manuela Gago-Dominguez, Esther M. John, Allison W. Kurian, Jenny Chang-Claude, Shou-Tung Chen, Thilo Dörk, D. Gareth R. Evans, Marjanka K. Schmidt, Min-Ho Shin, Graham G. Giles, Roger L. Milne, Jacques Simard, Michiaki Kubo, Peter Kraft, Daehee Kang, Douglas F. Easton, Wei Zheng, and Jirong Long
Subjects: Medicine, Medicine (General), R5-920
Abstract: Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P
Published: 2019
Full Text: View/download PDF

21. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019
Full Text: View/download PDF

22. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, and Georgia Chenevix-Trench
Subjects: Science
Abstract: Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.
Published: 2019
Full Text: View/download PDF

23. Health professionals’ perspectives on breast cancer risk stratification: understanding evaluation of risk versus screening for disease

Author: Svetlana Puzhko, Justin Gagnon, Jacques Simard, Bartha Maria Knoppers, Sophia Siedlikowski, and Gillian Bartlett
Subjects: Breast cancer screening, Deliberative stakeholder consultations, Risk stratification, Personalized screening, Program implementation, Public aspects of medicine, RA1-1270
Abstract: Abstract Background Younger women at higher-than-population-average risk for breast cancer may benefit from starting screening earlier than presently recommended by the guidelines. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) approach aims to improve the prevention of breast cancer through differential screening recommendations based on a personal risk estimate. In our study, we used deliberative stakeholder consultations to engage health professionals in an in-depth dialog to explore the feasibility of the proposed implementation strategies for this new personalized breast cancer screening approach. Methods Deliberative stakeholder consultation is a qualitative descriptive study design used to engage health professionals in the discussion, while the mediators play a more passive role. A purposeful sample of 11 health professionals (family physicians and genetic counselors) working in Montreal was used. The deliberations were organized in two phases, including small group deliberations according to the deliberants’ health profession and a mixed group deliberation combining participants from the small groups. Inductive thematic content analysis was performed on the transcripts by two coders to create the deliberative and analytic outputs. Quality of deliberations was assessed quantitatively using the de Vries method and qualitatively using participant observation. Results One of our key findings was that health professionals lacked understanding of the two steps of the screening approach: risk stratification “screening,” which is an evaluation for the level of risk and screening for disease. As part of this confusion, the main topic of concern was a justification of program implementation as a population-wide screening, based on their uncertainty that it will be beneficial for women with near-population risks. Despite the noted difficulties concerning implementation, health professionals acknowledged the substantial benefits of the proposed PERSPECTIVE program. Conclusions Our study was the first to evaluate the perspectives of health professionals on the implementation and benefits of a new program for breast cancer risk stratification with the purpose of personalizing screening for disease. This new multi-step approach to screening requires more clarity in communication with health professionals. To implement and maintain effective screening, engagement of family physicians with other health professionals or even development of a centralized public health system may be needed.
Published: 2019
Full Text: View/download PDF

24. Organizational challenges to equity in the delivery of services within a new personalized risk-based approach to breast cancer screening

Author: Emmanuelle Lévesque, Julie Hagan, Bartha M. Knoppers, and Jacques Simard
Subjects: breast cancer, equity, screening, personalized medicine, Genetics, QH426-470, Medical philosophy. Medical ethics, R723-726
Abstract: Emerging evidence opens new possibilities to improve current breast cancer mammography screening programs. One promising avenue is to tailor mammography screening according to individual risk. However, some factors could challenge the implementation of such approach, specifically its potential impact on the equitable delivery of services. This study aims to identify the barriers and facilitators to the equitable delivery of services within a future integration of a personalized approach in the Québec screening program. We then propose different means to address them. We conducted 16 semi-structured interviews with stakeholders with a role in the management, implementation or assessment of the Québec screening program. The barriers and facilitators identified by respondents were regrouped in two themes: 1) Reproduction of social inequities, and 2) Amplification of regional disparities in access to services. We consider that fostering inclusion through communication strategies and relying on electronic communication technologies could help in addressing these issues.
Published: 2019
Full Text: View/download PDF

25. Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.
Published: 2019
Full Text: View/download PDF

26. Open science precision medicine in Canada: Points to consider

Author: Palmira Granados Moreno, Sarah E. Ali-Khan, Benjamin Capps, Timothy Caulfield, Damien Chalaud, Aled Edwards, E. Richard Gold, Vasiliki Rahimzadeh, Adrian Thorogood, Daniel Auld, Gabrielle Bertier, Felix Breden, Roxanne Caron, Priscilla M.D.G. César, Robert Cook-Deegan, Megan Doerr, Ross Duncan, Amalia M. Issa, Jerome Reichman, Jacques Simard, Derek So, Sandeep Vanamala, and Yann Joly
Subjects: open science, precision medicine, Canadian health policies, open science in precision medicine, valorisation, Education, Science
Abstract: Open science can significantly influence the development and translational process of precision medicine in Canada. Precision medicine presents a unique opportunity to improve disease prevention and healthcare, as well as to reduce health-related expenditures. However, the development of precision medicine also brings about economic challenges, such as costly development, high failure rates, and reduced market size in comparison with the traditional blockbuster drug development model. Open science, characterized by principles of open data sharing, fast dissemination of knowledge, cumulative research, and cooperation, presents a unique opportunity to address these economic challenges while also promoting the public good. The Centre of Genomics and Policy at McGill University organized a stakeholders’ workshop in Montreal in March 2018. The workshop entitled “Could Open be the Yellow Brick Road to Precision Medicine?” provided a forum for stakeholders to share experiences and identify common objectives, challenges, and needs to be addressed to promote open science initiatives in precision medicine. The rich presentations and exchanges that took place during the meeting resulted in this consensus paper containing key considerations for open science precision medicine in Canada. Stakeholders would benefit from addressing these considerations as to promote a more coherent and dynamic open science ecosystem for precision medicine.
Published: 2019
Full Text: View/download PDF

27. DSNetwork: An Integrative Approach to Visualize Predictions of Variants’ Deleteriousness

Author: Audrey Lemaçon, Marie-Pier Scott-Boyer, Régis Ongaro-Carcy, Penny Soucy, Jacques Simard, and Arnaud Droit
Subjects: fine-mapping analysis, variant prioritization, decision support, deleteriousness prediction, network visualization, Genetics, QH426-470
Abstract: One of the most challenging tasks of the post-genome-wide association studies (GWAS) research era is the identification of functional variants among those associated with a trait for an observed GWAS signal. Several methods have been developed to evaluate the potential functional implications of genetic variants. Each of these tools has its own scoring system, which forces users to become acquainted with each approach to interpret their results. From an awareness of the amount of work needed to analyze and integrate results for a single locus, we proposed a flexible and versatile approach designed to help the prioritization of variants by aggregating the predictions of their potential functional implications. This approach has been made available through a graphical user interface called DSNetwork, which acts as a single point of entry to almost 60 reference predictors for both coding and non-coding variants and displays predictions in an easy-to-interpret visualization. We confirmed the usefulness of our methodology by successfully identifying functional variants in four breast cancer and nine schizophrenia susceptibility loci.
Published: 2020
Full Text: View/download PDF

28. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Author: Marta Castroviejo‐Bermejo, Cristina Cruz, Alba Llop‐Guevara, Sara Gutiérrez‐Enríquez, Mandy Ducy, Yasir Hussein Ibrahim, Albert Gris‐Oliver, Benedetta Pellegrino, Alejandra Bruna, Marta Guzmán, Olga Rodríguez, Judit Grueso, Sandra Bonache, Alejandro Moles‐Fernández, Guillermo Villacampa, Cristina Viaplana, Patricia Gómez, Maria Vidal, Vicente Peg, Xavier Serres‐Créixams, Graham Dellaire, Jacques Simard, Paolo Nuciforo, Isabel T Rubio, Rodrigo Dienstmann, J Carl Barrett, Carlos Caldas, José Baselga, Cristina Saura, Javier Cortés, Olivier Déas, Jos Jonkers, Jean‐Yves Masson, Stefano Cairo, Jean‐Gabriel Judde, Mark J O'Connor, Orland Díez, Judith Balmaña, and Violeta Serra
Subjects: BRCA1, homologous recombination, PALB2, PARP inhibitors, RAD51, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.
Published: 2018
Full Text: View/download PDF

29. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4
Published: 2021
Full Text: View/download PDF

30. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Author: Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, GEMO Study Collaborators, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, EMBRACE, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, KConFab Investigators, Australian Ovarian Cancer Study Group, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, and Simon A. Gayther
Subjects: Science
Abstract: A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
Published: 2016
Full Text: View/download PDF

31. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Fergus J. Couch, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Gustavo A. Mendoza-Fandino, Silje Nord, Janna Lilyquist, Curtis Olswold, Emily Hallberg, Simona Agata, Habibul Ahsan, Kristiina Aittomäki, Christine Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Lars Beckmann, Matthias W. Beckmann, Javier Benitez, Stephanie V. Blank, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Federico Canzian, Jane Carpenter, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Miguel de la Hoya, Peter Devilee, Orland Diez, Yuan C. Ding, Riccardo Dolcetti, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Martine Dumont, Alison M. Dunning, Diana M. Eccles, Hans Ehrencrona, Arif B. Ekici, Heather Eliassen, Steve Ellis, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Asta Försti, Florentia Fostira, William D. Foulkes, Tara Friebel, Eitan Friedman, Debra Frost, Marike Gabrielson, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Mia M. Gaudet, Simon A. Gayther, Anne-Marie Gerdes, Maya Ghoussaini, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Marc Gunter, Lothar Haeberle, Christopher A. Haiman, Ute Hamann, Thomas V. O. Hansen, Steven Hart, Sue Healey, Tuomas Heikkinen, Brian E. Henderson, Josef Herzog, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Keith Humphreys, David J. Hunter, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Michael Jones, Maria Kabisch, Siddhartha Kar, Beth Y. Karlan, Sofia Khan, Kay-Tee Khaw, Muhammad G. Kibriya, Julia A. Knight, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Ava Kwong, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Eunjung Lee, Loic Le Marchand, Jenny Lester, Annika Lindblom, Noralane Lindor, Sara Lindstrom, Jianjun Liu, Jirong Long, Jan Lubinski, Phuong L. Mai, Enes Makalic, Kathleen E. Malone, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, John W. M. Martens, Lesley McGuffog, Alfons Meindl, Austin Miller, Roger L. Milne, Penelope Miron, Marco Montagna, Sylvie Mazoyer, Anna M. Mulligan, Taru A. Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Ana Osorio, Sue K. Park, Petra H. Peeters, Bernard Peissel, Paolo Peterlongo, Julian Peto, Catherine M. Phelan, Robert Pilarski, Bruce Poppe, Katri Pylkäs, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport, Gad Rennert, Andrea Richardson, Mark Robson, Isabelle Romieu, Anja Rudolph, Emiel J. Rutgers, Maria-Jose Sanchez, Regina M. Santella, Elinor J. Sawyer, Daniel F. Schmidt, Marjanka K. Schmidt, Rita K. Schmutzler, Fredrick Schumacher, Rodney Scott, Leigha Senter, Priyanka Sharma, Jacques Simard, Christian F. Singer, Olga M. Sinilnikova, Penny Soucy, Melissa Southey, Doris Steinemann, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Csilla I. Szabo, Rulla Tamimi, William Tapper, Manuel R. Teixeira, Soo-Hwang Teo, Mary B. Terry, Mads Thomassen, Deborah Thompson, Laima Tihomirova, Amanda E. Toland, Robert A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Helen Tsimiklis, Alex Teulé, Rosario Tumino, Nadine Tung, Clare Turnbull, Giski Ursin, Carolien H. M. van Deurzen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Zhaoming Wang, Shan Wang-Gohrke, Elisabete Weiderpass, Jeffrey N. Weitzel, Alice Whittemore, Hans Wildiers, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Song Yao, M Pilar Zamora, Wei Zheng, Per Hall, Peter Kraft, Celine Vachon, Susan Slager, Georgia Chenevix-Trench, Paul D. P. Pharoah, Alvaro A. N. Monteiro, Montserrat García-Closas, Douglas F. Easton, and Antonis C. Antoniou
Subjects: Science
Abstract: Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
Published: 2016
Full Text: View/download PDF

32. Breast Cancer Risk Estimation and Personal Insurance: A Qualitative Study Presenting Perspectives from Canadian Patients and Decision Makers

Author: Gratien Dalpé, Ida Ngueng Feze, Shahad Salman, Yann Joly, Julie Hagan, Emmanuelle Lévesque, Véronique Dorval, Jolyane Blouin-Bougie, Nabil Amara, Michel Dorval, and Jacques Simard
Subjects: breast cancer, Canada, genetic testing, genetic discrimination, informed consent, insurability, Genetics, QH426-470
Abstract: Genetic stratification approaches in personalized medicine may considerably improve our ability to predict breast cancer risk for women at higher risk of developing breast cancer. Notwithstanding these advantages, concerns have been raised about the use of the genetic information derived in these processes, outside of the research and medical health care settings, by third parties such as insurers. Indeed, insurance applicants are asked to consent to insurers accessing their medical information (implicitly including genetic) to verify or determine their insurability level, or eligibility to certain insurance products. This use of genetic information may result in the differential treatment of individuals based on their genetic information, which could lead to higher premium, exclusionary clauses or even the denial of coverage. This phenomenon has been commonly referred to as “Genetic Discrimination” (GD). In the Canadian context, where federal Bill S-201, An Act to prohibit and prevent genetic discrimination, has recently been enacted but may be subject to constitutional challenges, information about potential risks to insurability may raise issues in the clinical context. We conducted a survey with women in Quebec who have never been diagnosed with breast cancer to document their perspectives. We complemented the research with data from 14 semi-structured interviews with decision-makers in Quebec to discuss institutional issues raised by the use of genetic information by insurers. Our results provide findings on five main issues: (1) the reluctance to undergo genetic screening test due to insurability concerns, (2) insurers' interest in genetic information, (3) the duty to disclose genetic information to insurers, (4) the disclosure of potential impacts on insurability before genetic testing, and (5) the status of genetic information compared to other health data. Overall, both groups of participants (the women surveyed and the decision-makers interviewed) acknowledged having concerns about GD and reported a need for better communication tools discussing insurability risk. Our conclusions regarding concerns about GD and the need for better communication tools in the clinical setting may be transferable to the broader Canadian context.
Published: 2017
Full Text: View/download PDF

33. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Author: Yan Guo, Shaneda Warren Andersen, Xiao-Ou Shu, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Montserrat Garcia-Closas, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Allison Dunning, Stig E Bojesen, Habibul Ahsan, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Natalia V Bogdanova, Bernardo Bonanni, Anne-Lise Børresen-Dale, Judith Brand, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Graham Casey, Georgia Chenevix-Trench, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Martine Dumont, Peter A Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Marilie Gammon, Graham G Giles, Pascal Guénel, Christopher A Haiman, Ute Hamann, Maartje J Hooning, John L Hopper, Anna Jakubowska, Farzana Jasmine, Mark Jenkins, Esther M John, Nichola Johnson, Michael E Jones, Maria Kabisch, Muhammad Kibriya, Julia A Knight, Linetta B Koppert, Veli-Matti Kosma, Vessela Kristensen, Loic Le Marchand, Eunjung Lee, Jingmei Li, Annika Lindblom, Robert Luben, Jan Lubinski, Kathi E Malone, Arto Mannermaa, Sara Margolin, Frederik Marme, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Susan L Neuhausen, Heli Nevanlinna, Patrick Neven, Janet E Olson, Jose I A Perez, Barbara Perkins, Paolo Peterlongo, Kelly-Anne Phillips, Katri Pylkäs, Anja Rudolph, Regina Santella, Elinor J Sawyer, Rita K Schmutzler, Caroline Seynaeve, Mitul Shah, Martha J Shrubsole, Melissa C Southey, Anthony J Swerdlow, Amanda E Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Giske Ursin, Rob B Van Der Luijt, Senno Verhoef, Alice S Whittemore, Robert Winqvist, Hui Zhao, Shilin Zhao, Per Hall, Jacques Simard, Peter Kraft, Paul Pharoah, David Hunter, Douglas F Easton, and Wei Zheng
Subjects: Medicine
Abstract: BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Published: 2016
Full Text: View/download PDF

34. 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
Full Text: View/download PDF

35. ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

Author: Anne-Laure Renault, Fabienne Lesueur, Yan Coulombe, Stéphane Gobeil, Penny Soucy, Yosr Hamdi, Sylvie Desjardins, Florence Le Calvez-Kelm, Maxime Vallée, Catherine Voegele, Breast Cancer Family Registry, John L Hopper, Irene L Andrulis, Melissa C Southey, Esther M John, Jean-Yves Masson, Sean V Tavtigian, and Jacques Simard
Subjects: Medicine, Science
Abstract: Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.
Published: 2016
Full Text: View/download PDF

36. RAD51B in Familial Breast Cancer.

Author: Liisa M Pelttari, Sofia Khan, Mikko Vuorela, Johanna I Kiiski, Sara Vilske, Viivi Nevanlinna, Salla Ranta, Johanna Schleutker, Robert Winqvist, Anne Kallioniemi, Thilo Dörk, Natalia V Bogdanova, Jonine Figueroa, Paul D P Pharoah, Marjanka K Schmidt, Alison M Dunning, Montserrat García-Closas, Manjeet K Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, John L Hopper, Melissa C Southey, Efraim H Rosenberg, Peter A Fasching, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Harald Surowy, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Javier Benitez, Anna González-Neira, Susan L Neuhausen, Hoda Anton-Culver, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Thomas Brüning, Annika Lindblom, Sara Margolin, Arto Mannermaa, Jaana M Hartikainen, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Laurien Van Dyck, Hilde Janssen, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Emily Hallberg, Janet E Olson, Graham G Giles, Roger L Milne, Christopher A Haiman, Fredrick Schumacher, Jacques Simard, Martine Dumont, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Alicia Beeghly-Fadiel, Mervi Grip, Irene L Andrulis, Gord Glendon, Peter Devilee, Caroline Seynaeve, Maartje J Hooning, Margriet Collée, Angela Cox, Simon S Cross, Mitul Shah, Robert N Luben, Ute Hamann, Diana Torres, Anna Jakubowska, Jan Lubinski, Fergus J Couch, Drakoulis Yannoukakos, Nick Orr, Anthony Swerdlow, Hatef Darabi, Jingmei Li, Kamila Czene, Per Hall, Douglas F Easton, Johanna Mattson, Carl Blomqvist, Kristiina Aittomäki, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Published: 2016
Full Text: View/download PDF

37. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Author: Hisani N Horne, Charles C Chung, Han Zhang, Kai Yu, Ludmila Prokunina-Olsson, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hiroji Iwata, Thilo Dörk, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Anna H Wu, David Ven den Berg, Ann Smeets, Hui Zhao, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Monica Barile, Fergus J Couch, Celine Vachon, Graham G Giles, Roger L Milne, Christopher A Haiman, Loic Le Marchand, Mark S Goldberg, Soo H Teo, Nur A M Taib, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Martha Shrubsole, Robert Winqvist, Arja Jukkola-Vuorinen, Irene L Andrulis, Julia A Knight, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Kamila Czene, Hatef Darabi, Antoinette Hollestelle, John W M Martens, Jingmei Li, Wei Lu, Xiao-Ou Shu, Angela Cox, Simon S Cross, William Blot, Qiuyin Cai, Mitul Shah, Craig Luccarini, Caroline Baynes, Patricia Harrington, Daehee Kang, Ji-Yeob Choi, Mikael Hartman, Kee Seng Chia, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, Paul Brennan, Susan Slager, Drakoulis Yannoukakos, Chen-Yang Shen, Ming-Feng Hou, Anthony Swerdlow, Nick Orr, Jacques Simard, Per Hall, Paul D P Pharoah, Douglas F Easton, Stephen J Chanock, Alison M Dunning, and Jonine D Figueroa
Subjects: Medicine, Science
Abstract: The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
Published: 2016
Full Text: View/download PDF

38. 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
Full Text: View/download PDF

39. Characterization of a novel mutation causing hepatic lipase deficiency among French Canadians

Author: Isabelle L. Ruel, Patrick Couture, Claude Gagné, Yves Deshaies, Jacques Simard, Robert A. Hegele, and Benoît Lamarche
Subjects: lipid, lipoprotein, metabolism, abdominal obesity, Biochemistry, QD415-436
Abstract: Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides (TGs) and cholesterol. The aim of the present study was to characterize the molecular defect leading to severe HL deficiency in a Québec-based kindred. In the proband and two of her brothers, the very low to undetectable HL activity resulted from compound heterozygosity for two rare HL gene mutations, a previously unknown missense mutation in exon 5 designated A174T and the previously reported T383M mutation in exon 8 of the HL gene. The mutation at codon 174 resulted in the substitution of alanine for threonine, a polar amino acid, in a highly conserved nonpolar region of the protein involved in the catalytic activity of the enzyme. The severe HL deficiency among the three related compound heterozygotes was associated with a marked TG enrichment of LDL and HDL particles. The two men with severe HL deficiency also presented with abdominal obesity, which appeared to amplify the impact of HL deficiency on plasma TG-rich lipoprotein levels.Our results demonstrated that HL deficiency in this Québec kindred is associated with an abnormal lipoprotein-lipid profile, which may vary considerably in the presence of secondary factors such as abdominal obesity.
Published: 2003
Full Text: View/download PDF

40. 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
Full Text: View/download PDF

41. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author: Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas
Subjects: Genetics, QH426-470
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P
Published: 2014
Full Text: View/download PDF

42. MicroRNA related polymorphisms and breast cancer risk.

Author: Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, kConFab Investigators, Australian Ovarian Cancer Study Group, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, GENICA Network, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Published: 2014
Full Text: View/download PDF

43. Response of Symbiotic Endomycorrhizal Fungi to Estrogens and Antiestrogens

Author: Marie-Josée Poulin, Jacques Simard, Jean-Guy Catford, Fernand Librie, and Yves Piché
Subjects: estrogenic activity, Microbiology, QR1-502, Botany, QK1-989
Abstract: Plant flavonoids reported previously to act as molecular signals in the arbuscular mycorrhizal (AM) symbiosis are known to bind to estrogen receptors and to exert estrogenic effects on mammalian cells. To further investigate the estrogen-like properties of flavonoids the present study examined whether estrogen and antiestrogens have fla-vonoid-related functions in AM fungi. Bioassays were performed in a monoaxenic system with the AM fungi Giga-spora margarita and Glomus intraradices. The plant flavo-noids quercetin and biochanin A stimulate hyphal growth of G. margarita and G. intraradices, respectively. The stimulatory activity of biochanin A studied at concentrations ranging from 0.01 to 10.0 μM shows an estimated EC50 value of 3.26 μM. The present results show that 17β-estradiol and biochanin A exert similar stimulatory effects in G. intraradices. The agonist effect of biochanin A was efficiently suppressed by the new antiestrogen EM-652, which is also consistent with the possible presence of estrogen-binding sites in AM fungi.
Published: 1997
Full Text: View/download PDF

44. 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
Full Text: View/download PDF

45. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author: Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, KConFab Investigators, Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Ontario Cancer Genetics Network, Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, GEMO Study Collaborators, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, GENICA Network, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, and Kenneth Offit
Subjects: Genetics, QH426-470
Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Published: 2013
Full Text: View/download PDF

46. Canadian Healthcare Professionals’ Views and Attitudes toward Risk-Stratified Breast Cancer Screening

Author: Nabi, Julie Lapointe, Jean-Martin Côté, Cynthia Mbuya-Bienge, Michel Dorval, Nora Pashayan, Jocelyne Chiquette, Laurence Eloy, Annie Turgeon, Laurence Lambert-Côté, Jennifer D. Brooks, Meghan J. Walker, Kristina Maria Blackmore, Yann Joly, Bartha Maria Knoppers, Anna Maria Chiarelli, Jacques Simard, and Hermann
Subjects: breast cancer, health policies, health professionals, implementation, national health systems, perspectives, personalized screening, risk-based strategy, screening programs
Abstract: Given the controversy over the effectiveness of age-based breast cancer (BC) screening, offering risk-stratified screening to women may be a way to improve patient outcomes with detection of earlier-stage disease. While this approach seems promising, its integration requires the buy-in of many stakeholders. In this cross-sectional study, we surveyed Canadian healthcare professionals about their views and attitudes toward a risk-stratified BC screening approach. An anonymous online questionnaire was disseminated through Canadian healthcare professional associations between November 2020 and May 2021. Information collected included attitudes toward BC screening recommendations based on individual risk, comfort and perceived readiness related to the possible implementation of this approach. Close to 90% of the 593 respondents agreed with increased frequency and earlier initiation of BC screening for women at high risk. However, only 9% agreed with the idea of not offering BC screening to women at very low risk. Respondents indicated that primary care physicians and nurse practitioners should play a leading role in the risk-stratified BC screening approach. This survey identifies health services and policy enhancements that would be needed to support future implementation of a risk-stratified BC screening approach in healthcare systems in Canada and other countries.
Published: 2023
Full Text: View/download PDF

47. Perceptions and Usability of PREVENTION: A Breast Cancer Risk Assessment e-Platform

Author: Samar Attieh, Marika Monarque, Andrew Durand, Saima Ahmed, Bartha M. Knoppers, Jacques Simard, and Carmen G. Loiselle
Subjects: breast cancer, e-health, prevention, risk assessment, risk stratification, screening, e-platform usability, Medicine (miscellaneous)
Abstract: Background: The PREVENTION e-platform was developed to provide accessible and evidence-based health information tailored to different Breast Cancer (BC) risk levels. The demonstration study objectives were to (1) assess the usability and perceived impact of PREVENTION on women with assigned hypothetical BC risk levels (i.e., near population, intermediate or high) and (2) explore perceptions and recommendations for e-platform improvement. Methods: Thirty women with no history of cancer were recruited through social media, commercial centers, health clinics, and community settings in Montreal, Qc, Canada. Participants accessed e-platform content tailored to their assigned hypothetical BC risk level, and then completed study e-questionnaires including the user Mobile Application Rating Scale (uMARS), an e-platform quality scale (i.e., in terms of engagement, functionality, aesthetics, and information). A subsample (n = 18) was randomly selected for an individual follow-up semi-structured interview. Results: The e-platform overall quality was high, with mean M = 4.01 (out of 5) and SD = 0.50. A total of 87% (n = 26) agreed or strongly agreed that PREVENTION increased their knowledge and awareness of BC risk, and 80% would recommend it to others while reporting likelihood of following lifestyle recommendations to decrease their BC risk. Follow up interviews indicated that participants perceived the e-platform as a trusted source of BC information and a promising means to connect with peers. They also reported that while the e-platform was easy to navigate, improvements were needed for connectivity, visuals, and the organization of scientific resources. Conclusion: Preliminary findings support PREVENTION as a promising means to provide personalized BC information and support. Efforts are underway to further refine the platform, assess its impact in larger samples and gather feedback from BC specialists.
Published: 2023
Full Text: View/download PDF

48. Supplementary Tables 1-3 from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author: Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang
Abstract: Supplementary Table 1. Sample Size of each participated study, by case-control status and genotype platform. Supplementary Table 2. Association between fourteen environmental factors and the risk of breast cancer. Supplementary Table 3. Interactions between genes and fourteen environmental factors.
Published: 2023

49. Data from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author: Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang
Abstract: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this.We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test.After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6).In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk.Our study suggests a limited role of gene–environment interactions in breast cancer risk.
Published: 2023

50. Supplementary Information from A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author: Sara Lindström, Jenny Chang-Claude, Peter Kraft, Li Hsu, Roger L. Milne, Douglas F. Easton, Håkan Olsson, Sophia Wang, James V. Lacey, Nick Orr, Anthony J. Swerdlow, Jack A. Taylor, Dale P. Sandler, Alicja Wolk, Kamila Czene, Per Hall, Anthony Howell, D. Gareth Evans, Rose Yang, Thomas Ahearn, Jonine Figueroa, Montserrat García-Closas, Heather Eliassen, Rulla Tamimi, Cheng Peng, Michael I. Love, Melissa A. Troester, Jirong Long, Wei Zheng, Mark S. Goldberg, Jacques Simard, Stacey Winham, Christopher Scott, Gertraud Maskarinec, Christopher A. Haiman, Graham G. Giles, Heiko Becher, Audrey Jung, Veli-Matti Kosma, Arto Mannermaa, Sabine Behrens, Wing-Yee Lo, Reiner Hoppe, Volker Arndt, Hermann Brenner, Rudolf Kaaks, Federico Canzian, James M. Hodge, Lauren R. Teras, Thérèse Truong, Pascal Guénel, Kristan Aronson, Rachel A. Murphy, Rana Shibli, Gad Rennert, Jennifer Stone, Laura E. Beane Freeman, Stella Koutros, Melissa C. Southey, John L. Hopper, Paul D.P. Pharoah, Kyriaki Michailidou, Qin Wang, Michael Lush, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Yu-Ru Su, Pooja Middha Kapoor, Hongjie Chen, and Xiaoliang Wang
Abstract: Funding and acknowledgements.
Published: 2023

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Category

Publication Type

Journal

Database

Publisher

486 results on '"Jacques Simard"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources