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1. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author

Anna Morra, Maartje A. C. Schreurs, Irene L. Andrulis, Hoda Anton‐Culver, Annelie Augustinsson, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Annegien Broeks, Saundra S. Buys, Nicola J. Camp, Jose E. Castelao, Melissa H. Cessna, Jenny Chang‐Claude, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Tanja N. Fehm, Jonine D. Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago‐Dominguez, Montserrat García‐Closas, José A. García‐Sáenz, Jeanine Genkinger, Felix Grassmann, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, ABCTB Investigators, kConFab Investigators, Anna Jakubowska, Wolfgang Janni, Helena Jernström, Esther M. John, Nichola Johnson, Michael E. Jones, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Michael P. Lux, Arto Mannermaa, Dimitrios Mavroudis, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, Ines Nevelsteen, Patrick Neven, William G. Newman, Nadia Obi, Kenneth Offit, Andrew F. Olshan, Tjoung‐Won Park‐Simon, Alpa V. Patel, Paolo Peterlongo, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Eric C. Polley, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Muhammad U. Rashid, Valerie Rhenius, Mark Robson, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Sabine Schuetze, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, William J. Tapper, Lauren R. Teras, Rob A. E. M. Tollenaar, Katarzyna Tomczyk, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Elke M. vanVeen, Qin Wang, Camilla Wendt, Hans Wildiers, Robert Winqvist, Argyrios Ziogas, Per Hall, Paul D. P. Pharoah, Muriel A. Adank, Antoinette Hollestelle, Marjanka K. Schmidt, and Maartje J. Hooning

Subjects
CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Published
2023
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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
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3. 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
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4. 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
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5. A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Author

Camilla Wendt, Taru A. Muranen, Lotta Mielikäinen, Jessada Thutkawkorapin, Carl Blomqvist, Xiang Jiao, Hans Ehrencrona, Emma Tham, Brita Arver, Beatrice Melin, Ekaterina Kuchinskaya, Marie Stenmark Askmalm, Ylva Paulsson-Karlsson, Zakaria Einbeigi, Anna von Wachenfeldt Väppling, Eija Kalso, Tiina Tasmuth, Anne Kallioniemi, Kristiina Aittomäki, Heli Nevanlinna, Åke Borg, and Annika Lindblom

Subjects
Medicine, Science
Abstract

Abstract The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

Published
2021
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6. 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
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7. A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

Author

Elin Barnekow, Johan Hasslow, Wen Liu, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin, and Annika Lindblom

Subjects
GWAS, breast cancer, haplotype, familial, risk loci, SMARCA2, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

Published
2023
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8. Prediction and clinical utility of a contralateral breast cancer risk model

Author

Daniele Giardiello, Ewout W. Steyerberg, Michael Hauptmann, Muriel A. Adank, Delal Akdeniz, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Mariël Brinkhuis, Jenny Chang-Claude, Kamila Czene, Peter Devilee, Alison M. Dunning, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Montserrat García-Closas, Lothar Haeberle, Christopher A. Haiman, Per Hall, Ute Hamann, John L. Hopper, Agnes Jager, Anna Jakubowska, Audrey Jung, Renske Keeman, Iris Kramer, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Mehdi Manoochehri, Luigi Mariani, Heli Nevanlinna, Hester S. A. Oldenburg, Saskia Pelders, Paul D. P. Pharoah, Mitul Shah, Sabine Siesling, Vincent T. H. B. M. Smit, Melissa C. Southey, William J. Tapper, Rob A. E. M. Tollenaar, Alexandra J. van den Broek, Carolien H. M. van Deurzen, Flora E. van Leeuwen, Chantal van Ongeval, Laura J. Van’t Veer, Qin Wang, Camilla Wendt, Pieter J. Westenend, Maartje J. Hooning, and Marjanka K. Schmidt

Subjects
Contralateral breast cancer, Risk prediction model, Clinical decision-making, BRCA mutation carriers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

Published
2019
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9. 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
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10. 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
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11. The impact of coding germline variants on contralateral breast cancer risk and survival

Author

Anna Morra, Nasim Mavaddat, Taru A. Muranen, Thomas U. Ahearn, Jamie Allen, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Sabine Behrens, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Nicola J. Camp, Sara Carvalho, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Kamila Czene, Brennan Decker, Joe Dennis, Thilo Dörk, Leila Dorling, Alison M. Dunning, Arif B. Ekici, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Willemina R.R. Geurts-Giele, Graham G. Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia A. Harrington, Wei He, Päivi Heikkilä, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, Anna Jakubowska, Audrey Y. Jung, Renske Keeman, Vessela N. Kristensen, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Anna Marie Mulligan, William G. Newman, Tjoung-Won Park-Simon, Paolo Peterlongo, Paul D.P. Pharoah, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Amanda B. Spurdle, Ian Tomlinson, Thérèse Truong, Elke M. van Veen, Maaike P.G. Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R. Yang, Heli Nevanlinna, Peter Devilee, Douglas F. Easton, Marjanka K. Schmidt, Kristine K. Sahlberg, Anne-Lise Børresen-Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, null OSBREAC, Grethe I. Grenaker Alnæs, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, and Milita Zaheed

Subjects
Genetics, Genetics (clinical)
Abstract

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Published
2023

12. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author

Isabelle Grootes, Renske Keeman, Fiona M. Blows, Roger L. Milne, Graham G. Giles, Anthony J. Swerdlow, Peter A. Fasching, Mustapha Abubakar, Irene L. Andrulis, Hoda Anton-Culver, Matthias W. Beckmann, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ignacio Briceno, Barbara Burwinkel, Nicola J. Camp, Jose E. Castelao, Ji-Yeob Choi, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, Kristina Ernst, D. Gareth Evans, Jonine D. Figueroa, Visnja Fink, Giuseppe Floris, Stephen Fox, Marike Gabrielson, Manuela Gago-Dominguez, José A. García-Sáenz, Anna González-Neira, Lothar Haeberle, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Mikael Hartman, Alexander Hein, Maartje J. Hooning, Ming-Feng Hou, Sacha J. Howell, Hidemi Ito, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Jung, Daehee Kang, Vessela N. Kristensen, Ava Kwong, Diether Lambrechts, Jingmei Li, Jan Lubiński, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Nur Aishah Mohd Taib, Anna Marie Mulligan, Heli Nevanlinna, William G. Newman, Kenneth Offit, Ana Osorio, Sue K. Park, Tjoung-Won Park-Simon, Alpa V. Patel, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Gad Rennert, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Andreas Schneeweiss, Fabienne Schochter, Minouk J. Schoemaker, Chen-Yang Shen, Rana Shibli, Peter Sinn, William J. Tapper, Essa Tawfiq, Soo Hwang Teo, Lauren R. Teras, Diana Torres, Celine M. Vachon, Carolien H.M. van Deurzen, Camilla Wendt, Justin A. Williams, Robert Winqvist, Mark Elwood, Marjanka K. Schmidt, Montserrat García-Closas, Paul D.P. Pharoah, Medical Oncology, Pathology, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, University of Helsinki, Helsinki University Hospital Area, Institute for Molecular Medicine Finland, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
Cancer Research, Breast Neoplasms/pathology, Manchester Cancer Research Centre, Receptor, ErbB-2, Receptors, Progesterone/metabolism, ResearchInstitutes_Networks_Beacons/mcrc, ADJUVANT TAMOXIFEN, 3122 Cancers, Receptor, ErbB-2/metabolism, Breast Neoplasms, PREDICT Breast, Prognosis, THERAPY, Progesterone receptor, Breast cancer, breast cancer, ESTROGEN-RECEPTOR, Oncology, SDG 3 - Good Health and Well-being, Humans, Female, CANCER PATIENTS, Receptors, Progesterone, Progesterone
Abstract

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Published
2022

13. A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16

Author

Elin Barnekow, Wen Liu, Hafdis T. Helgadottir, Kyriaki Michailidou, Joe Dennis, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin, and Annika Lindblom

Subjects
Cancer Research, BNIP3L, FGFR2, TOX3, CASC16, breast cancer, GWAS, haplotype, Cancer och onkologi, Oncology, Cancer and Oncology, Medical Genetics, Medicinsk genetik
Abstract

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population. De två första författarna delar förstaförfattarskapet.

Published
2022

14. Prediction and clinical utility of a contralateral breast cancer risk model

Author

William J. Tapper, Montserrat Garcia-Closas, Douglas F. Easton, Alison M. Dunning, Annika Lindblom, Rob A. E. M. Tollenaar, Hester S. A. Oldenburg, Per Hall, Chantal Van Ongeval, Diether Lambrechts, Daniele Giardiello, Agnes Jager, Jonine D. Figueroa, Melissa C. Southey, Qin Wang, Jan Lubinski, Ewout W. Steyerberg, Marjanka K. Schmidt, Manjeet K. Bolla, Anna Jakubowska, Paul D.P. Pharoah, Diana Eccles, Carl Blomqvist, Heli Nevanlinna, Flora E. van Leeuwen, Pieter J. Westenend, Mitul Shah, Iris Kramer, Luigi Mariani, Mehdi Manoochehri, Delal Akdeniz, Peter A. Fasching, Alexandra J. van den Broek, Muriel A. Adank, Saskia Pelders, Maartje J. Hooning, Christopher A. Haiman, Sabine Siesling, Loic Le Marchand, Peter Devilee, Michael Hauptmann, Ute Hamann, Jenny Chang-Claude, Camilla Wendt, Stig E. Bojesen, Lothar Haeberle, Mariël Brinkhuis, Laura J. van't Veer, Renske Keeman, Kamila Czene, Henrik Flyger, John L. Hopper, Audrey Y. Jung, Carolien H.M. van Deurzen, Vincent T.H.B.M. Smit, Health Technology & Services Research, Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Apollo - University of Cambridge Repository, Blomqvist, Carl [0000-0003-3041-1938], Department of Oncology, Clinicum, HUS Comprehensive Cancer Center, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Public Health, Medical Oncology, and Pathology

Subjects
Oncology, medicine.medical_treatment, BRCA mutation carriers, 0302 clinical medicine, Medizinische Fakultät, 3123 Gynaecology and paediatrics, Risk Factors, 030212 general & internal medicine, Family history, 10. No inequality, Netherlands, education.field_of_study, BRCA1 Protein, Area under the curve, Disease Management, Neoplasms, Second Primary, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, 3. Good health, Preventive mastectomy, 030220 oncology & carcinogenesis, Area Under Curve, Female, Disease Susceptibility, Mastectomy, Clinical decision-making, Research Article, medicine.medical_specialty, Population, 3122 Cancers, Breast Neoplasms, Risk Assessment, lcsh:RC254-282, 03 medical and health sciences, Germline mutation, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, education, Germ-Line Mutation, Proportional Hazards Models, BRCA2 Protein, business.industry, medicine.disease, Contralateral breast cancer, business, Risk prediction model
Abstract

Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

Published
2019

15. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study

Author

Joyce O'Shaughnessy, Susana Sousa, Josefina Cruz, Lesley Fallowfield, Päivi Auvinen, Catarina Pulido, Ana Cvetanovic, Sharon Wilks, Leonor Ribeiro, Mauricio Burotto, Dirk Klingbiel, Dimitri Messeri, Ari Alexandrou, Peter Trask, Judy Fredriksson, Zuzana Machackova, Ljiljana Stamatovic, Ernesto Korbenfeld, Jorge Nadal, Helio Pinczowski, Felipe J. Cruz, Gustavo Sousa, Aline C. Goncalves, Gisah Guilgen, Antti Jekunen, Winne Yeo, Chi K. Cheng, Hikmat A. Razeq, Fadi Karak, Fadi Farhat, Servando C. Huerta, Brizio M. Jaime, Juan Feregrino, Omar Castillo-Fernandez, Juan C. Alcedo, Maria Dionisio, Salha Bujassoum, Hatoon Bakhraibah, Alvaro R. Lescure, Camilla Wendt, Sara Margolin, Helena G. Björneklett, Michelina Cairo, Shaker Dakhil, Nguyet Le-Lindqwister, Ling Ma, Kristi J. McIntyre, Joyce O’Shaughnessy, Svetislava J. Vukelja, Donald Richards, and John Wallmark

Subjects
0301 basic medicine, Cancer Research, Receptor, ErbB-2, Phases of clinical research, Gastroenterology, Subcutaneous injection, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, Infusions, Intravenous, Adjuvant, Early breast cancer, Aged, 80 and over, Patient preference, Cross-Over Studies, Subcutaneous, Patient Preference, Fixed dose, Middle Aged, Neoadjuvant Therapy, Drug Combinations, Oncology, Chemotherapy, Adjuvant, Patient Satisfaction, 030220 oncology & carcinogenesis, Female, Pertuzumab, medicine.drug, Adult, Quality of life, medicine.medical_specialty, Injections, Subcutaneous, Fixed-dose combination, Breast Neoplasms, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Young Adult, Healthcare resource, Internal medicine, medicine, Humans, Adverse effect, Aged, Neoplasm Staging, Patient-reported outcomes, business.industry, Confidence interval, 030104 developmental biology, business
Abstract

Aim: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). Materials and methods: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. Results: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5–90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0–50.0 min with SC and 130.0–300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1–3 IV → cycles 4–6 SC: 77.5% → 72.5%; cycles 1–3 SC → cycles 4–6 IV: 77.5% → 63.8%). Conclusion: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.

Published
2021

16. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

Author

Kamila Czene, John L. Hopper, Audrey Y. Jung, William J. Tapper, Sabine Siesling, Camilla Wendt, Daniele Giardiello, Stig E. Bojesen, Michael Hauptmann, Maartje J. Hooning, Pieter J. Westenend, Alison M. Dunning, Diana Eccles, Peter Devilee, Linetta B. Koppert, Delal Akdeniz, Henrik Flyger, Chantal Van Ongeval, Luigi Mariani, Mitul Shah, Saskia Pelders, Muriel A. Adank, Agnes Jager, Jan Lubinski, Melissa C. Southey, Manjeet K. Bolla, Flora E. van Leeuwen, Carl Blomqvist, Anna Jakubowska, Paul D.P. Pharoah, Jenny Chang-Claude, Douglas F. Easton, Laura J. van't Veer, Renske Keeman, Qin Wang, Alexandra J. van den Broek, Hester S. A. Oldenburg, Carolien H.M. van Deurzen, Lothar Haeberle, Per Hall, Rob A. E. M. Tollenaar, Mariël Brinkhuis, Jonine D. Figueroa, Ute Hamann, J. Blom, Montserrat Garcia-Closas, Mehdi Manoochehri, Peter A. Fasching, Diether Lambrechts, Ewout W. Steyerberg, Iris Kramer, Marjanka K. Schmidt, Vincent T.H.B.M. Smit, Christopher A. Haiman, Loic Le Marchand, Annika Lindblom, Heli Nevanlinna, Public Health, and Medical Oncology

Subjects
0301 basic medicine, Cancer Research, IMPACT, Receptor, ErbB-2, Contralateral breast cancer, Cohort Studies, 0302 clinical medicine, Clinical decision making, Risk Factors, Validation, MUTATION, Mastectomy, CALIBRATION, education.field_of_study, Neoplasms, Second Primary, Prognosis, Risk prediction, 3. Good health, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Clinical decision-making, Adult, medicine.medical_specialty, MODELS, Population, Breast Neoplasms, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, In patient, education, Science & Technology, business.industry, External validation, International Agencies, medicine.disease, Confidence interval, 030104 developmental biology, business, Follow-Up Studies
Abstract

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making. ispartof: BREAST CANCER RESEARCH AND TREATMENT vol:181 issue:2 pages:423-434 ispartof: location:Netherlands status: published

Published
2020

17. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Risk, medicine.medical_specialty, Gene Expression, Genome-wide association study, Breast Neoplasms, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Expression quantitative trait loci, Medical genetics, Female, Gene expression, Breast Cancer Genetics, Genome-Wide Association Study
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Published
2019

18. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Wing-Yee Lo, Dhanya Ramachandran, Christos Petridis, Fernando Salvador Moreno, Tongguang Cheng, Bernardo Bonanni, Ann Smeets, Susan E. Hankinson, Caroline Seynaeve, Suet-Feung Chin, Vessela N. Kristensen, Christopher G. Scott, Javier Benitez, William T. Newman, Brigitte Rack, Marjanka K. Schmidt, Diether Lambrechts, Alfons Meindl, Maria Escala-Garcia, Hoda Anton-Culver, Veli-Matti Kosma, Nadege Presneau, Daniel F. Schmidt, Douglas F. Easton, Ans M.W. van den Ouweland, Emmanouil Saloustros, Antoinette Hollestelle, Darya Prokofieva, Elinor J. Sawyer, Louise A. Brinton, Manuela Gago-Dominguez, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Eva Galle, Catriona McLean, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Per Hall, Jaana M. Hartikainen, Leslie Bernstein, Jose Ignacio Arias Perez, Flavio Lejbkowicz, Qi Guo, Brian D. Carter, Martha S. Linet, Fredrick R. Schumacher, Yan Zhang, Mikael Eriksson, Hiltrud Brauch, Janet A. Dunn, Gord Glendon, Bernd Holleczek, William J. Tapper, Marike Gabrielson, Keith Humphreys, Rodney J. Scott, Tabea Kühl, Lorraine Durcan, David J. Hunter, Pascal Guénel, Tom Maishman, Mary B. Daly, Rami Nassir, Andreas Schneeweiss, Kamila Czene, Jonine D. Figueroa, Grethe I. Grenaker Alnæs, Julia A. Knight, Angel Carracedo, Susan M. Gapstur, Manuel R. Teixeira, Guanmengqian Huang, Paul L. Auer, Sara Y. Brucker, Johanna I. Kiiski, Adam R. Brentnall, Simon S. Cross, Joe Dennis, Nicola Miller, Walter C. Willett, Melissa C. Southey, Christoph Engel, Niclas Håkansson, Diana Eccles, John L. Hopper, Elaine F. Harkness, Audrey Y. Jung, Trinidad Caldés, Steven N. Hart, Sara Lindström, Michael P. Lux, Julie Lecarpentier, Lian Li, Robert Winqvist, Peter Kraft, Stephen J. Chanock, Thilo Dörk, Melanie Maierthaler, Rudolf Kaaks, Angela Cox, Maartje J. Hooning, José A. García-Sáenz, Christi J. van Asperen, Mervi Grip, Enes Makalic, Mia M. Gaudet, David E. Goldgar, Ross L. Prentice, Carolina Ellberg, Sune F. Nielsen, Federico Canzian, Rebecca Roylance, Aline Talhouk, Vassilios Georgoulias, Eunjung Lee, Siranoush Manoukian, Sara Margolin, Paul D.P. Pharoah, Hedy S. Rennert, Mitul Shah, Matthias W. Beckmann, Anthony Howell, Anne Lise Børresen-Dale, Christopher A. Haiman, V. Shane Pankratz, Anna González-Neira, Kathrin Thöne, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Ute Krüger, Mehdi Manoochehri, Arja Jukkola-Vuorinen, Loic Le Marchand, Katri Pylkäs, Peter Hillemanns, Dieter Flesch-Janys, Volker Arndt, Peter A. Fasching, Christine L. Clarke, Louise Hiller, Eric Hahnen, Jan Lubinski, Jose E. Castelao, Roger L. Milne, Linetta B. Koppert, Peter Devilee, Rob A. E. M. Tollenaar, Ian W. Brock, Claire Mulot, Mila Pinchev, Carlos Caldas, Michael Untch, Gadi Rennert, Aaron D. Norman, Per Broberg, Anthony J. Swerdlow, Lothar Haeberle, Heli Nevanlinna, Arto Mannermaa, Irene L. Andrulis, Angela George, Montserrat Garcia-Closas, Jolanta Lissowska, Jonathan Beesley, Paolo Peterlongo, Cari M. Kitahara, Rulla M. Tamimi, Annika Lindblom, Sabine Behrens, Nick Orr, David G. Cox, D. Gareth Evans, Jacques Simard, Diana Torres, Constance Turman, Celine M. Vachon, Qin Wang, Hans-Ulrich Ulmer, Maria Kabisch, Maria Elena Martinez, Paolo Radice, Maria Tengström, Dimitrios Mavroudis, Jean Abraham, Helena M. Earl, Alice S. Whittemore, Hermann Brenner, Rita K. Schmutzler, Børge G. Nordestgaard, Barbara Burwinkel, Michael Jones, Esther M. John, Patricia Harrington, Daniele Campa, Elke M. van Veen, Clara Pérez-Barrios, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Elza Khusnutdinova, Michael J. Kerin, Miriam Dwek, Sibylle Loibl, Manjeet K. Bolla, Carl Blomqvist, Sander Canisius, Graham G. Giles, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Emilie Cordina-Duverger, Arif B. Ekici, Yon-Dschun Ko, Pooja Middha, Alison M. Dunning, Katarzyna Kaczmarek, Bram Boeckx, Mary Beth Terry, Jenny Chang-Claude, Karoliona Prajzendanc, Renske Keeman, Camilla Wendt, Atocha Romero, Stig E. Bojesen, Robert J. MacInnis, Clare Turnbull, Lukas Schwentner, Xiaohong R. Yang, Henrik Flyger, Håkan Olsson, Wolfgang Janni, Sofia Khan, Clinicum, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUS Comprehensive Cancer Center, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, Cancer Research, PROGNOSIS, Genome-wide association study, PATHWAY, Prognostic markers, Breast cancer, 0302 clinical medicine, Epidemiology of cancer, Cancer genetics, RISK, Hazard ratio, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENETIC-VARIATION, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, SURVIVAL, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 7, EXPRESSION, medicine.medical_specialty, CLINICAL-OUTCOMES, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Article, White People, NBCS Collaborators, RC0254, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Proportional Hazards Models, business.industry, Proportional hazards model, Genetic Variation, Cancer, Bayes Theorem, medicine.disease, business, Genome-Wide Association Study
Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Published
2019

19. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Author

Qin Wang, kConFab, Paolo Radice, Tao Liu, Isabel dos-Santos-Silva, Douglas F. Easton, Joe Dennis, Qi Guo, Michael Lush, Jessada Thutkawkorapin, Diether Lambrechts, Barbara Kremeyer, Fergus J. Couch, Pascal Guénel, Melanie Gündert, Rita K. Schmutzler, William J. Blot, Julian Peto, Christine B. Ambrosone, Wei Zheng, Mikael Eriksson, Ute Hamann, Johanna Rantala, Barbara Burwinkel, Michael J. Kerin, Johanna Lundin, Graham G. Giles, Hiltrud Brauch, Hoda Anton-Culver, Veli-Matti Kosma, Marjanka K. Schmidt, Aocs Investigators, Paula Maguire, Marike Gabrielson, Judith S. Brand, Simone Picelli, Rajeshwari Marikkannu, Quan Du, Irene L. Andrulis, Valerie Rhenius, Kyriaki Michailidou, Susan L. Neuhausen, Vinaykumar Kontham, Alison M. Dunning, Hermann Brenner, Thilo Dörk, Elinor J. Sawyer, Christopher A. Haiman, Anna González-Neira, Thérèse Truong, Peter Devilee, Qiuyin Cai, Susanna von Holst, Peter A. Fasching, Anna Marie Mulligan, Bernardo Bonanni, Javier Benítez, Kamila Czene, Loic Le Marchand, Katri Pylkäs, Henrik Flyger, Jacques Simard, Manjeet K. Bolla, Alfons Meindl, Per Hall, Simon S. Cross, Annika Lindblom, Emily Hallberg, Christos Aravidis, Sara Margolin, Vessela N. Kristensen, Carl Blomqvist, Annegien Broeks, John W.M. Martens, Jonine D. Figueroa, Xiang Jiao, Montserrat Garcia-Closas, Mitul Shah, Matthias W. Beckmann, Thomas Brüning, Guanmengqian Huang, John L. Hopper, Jan Lubinski, Michael Jones, Anthony J. Swerdlow, Roger L. Milne, Patricia Harrington, Caroline Seynaeve, Arto Mannermaa, Liping Luo, Natalia Antonenkova, Tatjana Adamovic, Angela Cox, Maartje J. Hooning, Volker Arndt, Dieter Flesch-Janys, Camilla Wendt, Stig E. Bojesen, Melissa C. Southey, Robert Winqvist, Anna Jakubowska, Paul D.P. Pharoah, Bram Boeckx, Sandra Deming-Halverson, Heli Nevanlinna, Jenny Chang-Claude, School of Medicine / Clinical Medicine, Cardiology, Medical Oncology, Department of Oncology, Clinicum, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center

Subjects
EXPRESSION, 0301 basic medicine, Cellbiologi, 3122 Cancers, DNA-SEQUENCING DATA, Locus (genetics), Single-nucleotide polymorphism, Biology, Genome, FAMILIES, risk haplotype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, Genetic linkage, Journal Article, medicine, linkage analysis, Allele, Gene, WIDE LINKAGE SCAN, Genetics, Cancer och onkologi, MUTATIONS, familial breast cancer, Haplotype, LOCALIZATION, ASSOCIATION, sequencing, Cell Biology, medicine.disease, GENE, 3. Good health, GENOME, 030104 developmental biology, Oncology, DISCOVERY, Cancer and Oncology, 030220 oncology & carcinogenesis, Priority Research Paper
Abstract

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene., published version, peerReviewed

Published
2017

20. Production of Recombinant Peanut Allergen Ara h 2 using Lactococcus lactis

Author

Lars K Poulsen, Jacob Glenting, Søren M. Madsen, Helle W Sørensen, Kentaro Kato, Hanne Frøkiær, and Camilla Wendt

Subjects
Signal peptide, Signal peptidase, Expression vector, biology, Research, Lactococcus lactis, lcsh:QR1-502, Heterologous, food and beverages, Bioengineering, medicine.disease_cause, biology.organism_classification, Applied Microbiology and Biotechnology, lcsh:Microbiology, Microbiology, law.invention, Allergen, law, medicine, Recombinant DNA, biology.protein, Antibody, Biotechnology
Abstract

Background Natural allergen sources can supply large quantities of authentic allergen mixtures for use as immunotherapeutics. However, such extracts are complex, difficult to define, vary from batch to batch, which may lead to unpredictable efficacy and/or unacceptable levels of side effects. The use of recombinant expression systems for allergen production can alleviate some of these issues. Several allergens have been tested in high-level expression systems and in most cases show immunereactivity comparable to their natural counterparts. The gram positive lactic acid bacterium Lactococcus lactis is an attractive microorganism for use in the production of protein therapeutics. L. lactis is considered food grade, free of endotoxins, and is able to secrete the heterologous product together with few other native proteins. Hypersensitivity to peanut represents a serious allergic problem. Some of the major allergens in peanut have been described. However, for therapeutic usage more information about the individual allergenic components is needed. In this paper we report recombinant production of the Ara h 2 peanut allergen using L. lactis. Results A synthetic ara h 2 gene was cloned into an L. lactis expression plasmid containing the P170 promoter and the SP310mut2 signal sequence. Flask cultures grown overnight showed secretion of the 17 kDa Ara h 2 protein. A batch fermentation resulted in 40 mg/L recombinant Ara h 2. Purification of Ara h 2 from the culture supernatant was done by hydrophobic exclusion and size separation. Mass spectrometry and N-terminal analysis showed a recombinant Ara h 2 of full length and correctly processed by the signal peptidase. The immunological activity of recombinant Ara h 2 was analysed by ELISA using antibodies specific for native Ara h 2. The recombinant Ara h 2 showed comparable immunereactivity to that of native Ara h 2. Conclusion Recombinant production of Ara h 2 using L. lactis can offer high yields of secreted, full length and immunologically active allergen. The L. lactis expression system can support recombinant allergen material for immunotherapy and component resolved allergen diagnostics.

Published
2007

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