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

Author

Mueller, Stefanie H, Lai, Alvina G, Valkovskaya, Maria, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Abu-Ful, Zomoruda, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baert, Thais, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brucker, Sara Y, Buys, Saundra S, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Chung, Wendy K, NBCS Collaborators, Colonna, Sarah V, CTS Consortium, Cornelissen, Sten, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Yu-Tang, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Gentry-Maharaj, Aleksandra, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harkness, Elaine F, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, Hein, Alexander, Ho, Weang-Kee, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Huo, Dezheng, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Khusnutdinova, Elza K, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, and Kwong, Ava

Subjects
Genome-wide association study, Breast cancer susceptibility, Diverse ancestry, Clinical Sciences, ABCTB Investigators, Formins, Black People, Breast Neoplasms, Rare variants, Single Nucleotide, CTS Consortium, NBCS Collaborators, Gene regulation, Clinical Research, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Genetic Testing, Polymorphism, Aetiology, Genome-Wide Association Study, Cancer
Abstract

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. 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. In European ancestry samples, 14 genes were significantly associated (q

Published
2023

2. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author

Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U, Antonenkova, Natalia N, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J, Bogdanova, Natalia V, Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J, Campbell, Archie, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, NBCS Collaborators, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine D, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, KConFab Investigators, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K, Ko, Yon-Dschun, Kristensen, Vessela N, Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G, Obi, Nadia, Panayiotidis, Mihalis I, Rashid, Muhammad U, Rhenius, Valerie, Rookus, Matti A, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Shah, Mitul, Sironen, Reijo, Southey, Melissa C, Suvanto, Maija, Tollenaar, Rob AEM, Tomlinson, Ian, Truong, Thérèse, Van Der Kolk, Lizet E, Van Veen, Elke M, Wappenschmidt, Barbara, Yang, Xiaohong R, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Easton, Douglas F, Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul DP, Wang, Qin, Adank, Muriel A, Schmidt, Marjanka K, Andrulis, Irene L, Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D Gareth, Milne, Roger L, Radice, Paolo, Peterlongo, Paolo, Figlioli, Gisella [0000-0002-0740-1363], Becher, Heiko [0000-0002-8808-6667], Behrens, Sabine [0000-0002-9714-104X], Blok, Marinus J [0000-0002-7935-5933], Bonanni, Bernardo [0000-0003-3589-2128], Chanock, Stephen J [0000-0002-2324-3393], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Fasching, Peter A [0000-0003-4885-8471], Grassmann, Felix [0000-0003-1390-7528], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Lissowska, Jolanta [0000-0003-2695-5799], Newman, William G [0000-0002-6382-4678], Panayiotidis, Mihalis I [0000-0002-1450-3552], Rashid, Muhammad U [0000-0002-7684-3122], Saloustros, Emmanouil [0000-0002-0485-0120], Yang, Xiaohong R [0000-0003-4451-8664], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Michailidou, Kyriaki [0000-0001-7065-1237], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Andrulis, Irene L [0000-0002-4226-6435], Nevanlinna, Heli [0000-0002-0916-2976], Milne, Roger L [0000-0001-5764-7268], Radice, Paolo [0000-0001-6298-4111], Peterlongo, Paolo [0000-0001-6951-6855], and Apollo - University of Cambridge Repository

Subjects
DNA Helicases, Humans, Female, Breast Neoplasms, Triple Negative Breast Neoplasms, Genetic Predisposition to Disease, KConFab Investigators, NBCS Collaborators
Abstract

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

Published
2022
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3. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Dennis, Joe, Tyrer, Jonathan, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Jean, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Kristensen, Vessela N, Sahlberg, Kristine K, Børresen-Dale, Anne-Lise, Gram, Inger Torhild, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, Alnæs, Grethe I Grenaker, Collée, J Margriet, Lacey, James, Martinez, Elena, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Clarke, Christine, Carpenter, Jane, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Campbell, Ian, De Fazio, Anna, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Milne, Roger, Southey, Melissa, Spurdle, Amanda, Thorne, Heather, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, Soucy, Penny, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wendt, Camilla, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Simard, Jacques, Dunning, Alison, Pharoah, Paul, Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Jean [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Kristensen, Vessela N [0000-0001-5012-7438], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Wilson, Leila [0000-0003-1214-8080], Clinical Genetics, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum

Subjects
endocrine system diseases, 45/43, Medicine (miscellaneous), Genome-wide association studies, Basic medicine, Breast cancer, Other medical sciences, Runx2, Risk Factors, Biology (General), skin and connective tissue diseases, 0303 health sciences, 030305 genetics & heredity, article, 3. Good health, Female, General Agricultural and Biological Sciences, Medical Genetics, Mutations, DNA Copy Number Variations, Locus, QH301-705.5, kConFab/AOCS Investigators, ABCTB Investigators, 631/208/205/2138, Breast Neoplasms, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, NBCS Collaborators, Association, Deletion, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Humans, 030304 developmental biology, Medicinsk genetik, Cancer och onkologi, Genome, Human, Health sciences, 631/67/1347, CTS Consortium, Germ Cells, Genes, Clinical medicine, Cancer and Oncology, Case-Control Studies, 3111 Biomedicine, Structural variation, Brca1, Genome-Wide Association Study
Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value, 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
2021

4. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author

Park, Hanla A, Neumeyer, Sonja, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baten, Adinda, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny, Harkness, Elaine F, Hart, Steven N, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hopper, John L, Hunter, David J, ABCTB Investigators, kConFab Investigators, Jager, Agnes, Jakubowska, Anna, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lo, Wing-Yee, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Meindl, Alfons, and Menon, Usha

Subjects
Genotyping Techniques, Oncology and Carcinogenesis, ABCTB Investigators, Breast Neoplasms, NBCS Collaborators, Cigarette Smoking, Substance Misuse, Clinical Research, Breast Cancer, Tobacco, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Aetiology, Cancer, Tobacco Smoke and Health, Prevention, Human Genome, Substance Abuse, Genetic Pleiotropy, Single Nucleotide, Mendelian Randomization Analysis, Good Health and Well Being, Case-Control Studies, Public Health and Health Services, kConFab Investigators, Female, Drug Abuse (NIDA only), Genome-Wide Association Study
Abstract

BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

Published
2021

5. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author

Morra, Anna, Escala-Garcia, Maria, Beesley, Jonathan, Keeman, Renske, Canisius, Sander, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Caan, Bette, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Ting-Yuan David, Clarke, Christine L, NBCS Collaborators, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Dörk, Thilo, Dossus, Laure, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, Gago-Dominguez, Manuela, García-Sáenz, José A, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Hartikainen, Jaana M, Hartmann, Arndt, He, Wei, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab Investigators, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Keupers, Machteld, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Linet, Martha, Luben, Robert N, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martens, John WM, Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L, Mulligan, Anna Marie, and Muranen, Taru A

Subjects
Oncology and Carcinogenesis, ABCTB Investigators, Breast Neoplasms, Systemic treatment, NBCS Collaborators, Clinical Research, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Polymorphism, Aetiology, Germ-Line Mutation, Cancer, Tumor biology, Human Genome, Single Nucleotide, Common germline genetic variants, Prognosis, Survival Analysis, kConFab Investigators, Female, Patient subgroups, Genome-Wide Association Study, Breast cancer-specific survival
Abstract

BackgroundGiven the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.MethodsWe performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP

Published
2021

6. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author

Baxter, Joseph S, Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Brucker, Sara Y, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, NBCS Collaborators, Colonna, Sarah, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, García-Closas, Montserrat, García-Sáenz, José A, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hou, Ming-Feng, kConFab Investigators, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, and Lacey, James V

Subjects
ABCTB Investigators, Breast Neoplasms, Medical and Health Sciences, Chromosomes, Cell Line, NBCS Collaborators, Promoter Regions, breast cancer risk, Genetic, Risk Factors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Genetic Association Studies, Sequence Deletion, Cancer, Genetics & Heredity, Prevention, Human Genome, Chromosome Mapping, Genetic Variation, Molecular Sequence Annotation, functional annotation, Biological Sciences, Estrogen, risk locus, Pair 2, kConFab Investigators, Female, CRISPR-Cas Systems, Insulin-Like Growth Factor Binding Protein 5, Human
Abstract

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with invitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1× 10-31).

Published
2021

7. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E., Schoemaker, Minouk J., Gilham, Clare, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E. Beane, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Dörk, Thilo, Eliassen, A. Heather, Engel, Christoph, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., Hooning, Maartje J., Hopper, John L., Howell, Anthony, Hunter, David J., Jager, Agnes, Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Obi, Nadia, Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S., Ruddy, Kathryn J., Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Tamimi, Rulla M., Taylor, Jack A., Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., van Veen, Elke M., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D. P., Easton, Douglas F., Howie, A. Forbes, Peto, Julian, dos-Santos-Silva, Isabel, Swerdlow, Anthony J., Chang-Claude, Jenny, Schmidt, Marjanka K., Orr, Nick, Fletcher, Olivia, Børresen-Dale, Anne-Lise, Alnæs, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Bowtell, David D. L., deFazio, Anna, Webb, Penelope M., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, O’Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, Young, Mary Ann, Johnson, Nichola [0000-0002-8230-5662], Kapoor, Pooja Middha [0000-0001-5503-8215], Dennis, Joe [0000-0003-4591-1214], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Fasching, Peter A. [0000-0003-4885-8471], Hart, Steven N. [0000-0001-7714-2734], Jakubowska, Anna [0000-0002-5650-0501], Kurian, Allison W. [0000-0002-6175-9470], Peterlongo, Paolo [0000-0001-6951-6855], Sawyer, Elinor J. [0000-0001-8285-4111], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], Peto, Julian [0000-0002-1685-8912], Apollo - University of Cambridge Repository, Medical Oncology, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Fasching, Peter A [0000-0003-4885-8471], Hart, Steven N [0000-0001-7714-2734], Kurian, Allison W [0000-0002-6175-9470], Sawyer, Elinor J [0000-0001-8285-4111], and Pharoah, Paul DP [0000-0001-8494-732X]

Subjects
Cancer Research, CYP3A5, Physiology, Genome-wide association study, Breast cancer, 0302 clinical medicine, Epidemiology, Receptors, IMPUTATION, Medicine, Cytochrome P-450 CYP3A, Cancer genetics, Progesterone, 0303 health sciences, article, 1112 Oncology and Carcinogenesis, 1117 Public Health and Health Services, AOCS Group, Single Nucleotide, humanities, 3. Good health, Receptors, Estrogen, Oncology, Hormone receptor, 030220 oncology & carcinogenesis, kConFab Investigators, Pregnanediol, Female, Receptors, Progesterone, Medical Genetics, medicine.medical_specialty, Estrone, Urinary system, 3122 Cancers, ABCTB Investigators, 631/67/2324, Breast Neoplasms, Polymorphism, Single Nucleotide, NBCS Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, 631/67/68, Humans, Oncology & Carcinogenesis, Allele, GENOME-WIDE ASSOCIATION, Polymorphism, CYP3A7, Alleles, 030304 developmental biology, Medicinsk genetik, business.industry, 631/67/1347, medicine.disease, Case-Control Studies, Genome-Wide Association Study, Premenopause, Estrogen, business, Hormone
Abstract

Background Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Published
2021

8. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, AOCS Group, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab Investigators, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, and Nielsen, Sune F

Subjects
Aging, Estrone, Oncology and Carcinogenesis, ABCTB Investigators, Breast Neoplasms, NBCS Collaborators, Clinical Research, Receptors, Breast Cancer, Genetics, Humans, Cytochrome P-450 CYP3A, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Polymorphism, Aetiology, Progesterone, Alleles, Cancer, Human Genome, Single Nucleotide, AOCS Group, Estrogen, Premenopause, Case-Control Studies, Public Health and Health Services, Pregnanediol, kConFab Investigators, Female, Genome-Wide Association Study
Abstract

BackgroundEpidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.MethodsWe carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.ResultsFor pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).ConclusionsThe CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Published
2021

9. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Author

Iris Kramer, Maartje J. Hooning, Nasim Mavaddat, Michael Hauptmann, Renske Keeman, Ewout W. Steyerberg, Daniele Giardiello, Antonis C. Antoniou, Paul D.P. Pharoah, Sander Canisius, Zumuruda Abu-Ful, Irene L. Andrulis, Hoda Anton-Culver, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Michael Bremer, Sara Y. Brucker, Barbara Burwinkel, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ji-Yeob Choi, Christine L. Clarke, J. Margriet Collée, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Graham G. Giles, David E. Goldgar, Anna González-Neira, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Mikael Hartman, Bernadette A.M. Heemskerk-Gerritsen, Antoinette Hollestelle, John L. Hopper, Ming-Feng Hou, Anthony Howell, Hidemi Ito, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Jung, Daehee Kang, C. Marleen Kets, Elza Khusnutdinova, Yon-Dschun Ko, Vessela N. Kristensen, Allison W. Kurian, Ava Kwong, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Tjoung-Won Park-Simon, Julian Peto, Christos Petridis, Dijana Plaseska-Karanfilska, Nadege Presneau, Katri Pylkäs, Paolo Radice, Gad Rennert, Atocha Romero, Rebecca Roylance, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Mee-Hoong See, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Sabine Siesling, Susan Slager, Christof Sohn, Melissa C. Southey, John J. Spinelli, Jennifer Stone, William J. Tapper, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Rob A.E.M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Chantal van Ongeval, Elke M. van Veen, Robert Winqvist, Alicja Wolk, Wei Zheng, Argyrios Ziogas, Douglas F. Easton, Per Hall, Marjanka K. Schmidt, Anne-Lise Børresen-Dale, Kristine Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile Kiserud, Kristin Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, Grethe Grenaker Alnæs, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J. Dinny Graham, Mythily Sachchithananthan, 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, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, 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, Geoff Lindeman, Lara Lipton, Liz Lobb, Graham Mann, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Edwina Rickard, Bridget Robinson, Mona Saleh, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Clare Scott, Adrienne Sexton, Andrew Shelling, 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, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Medical Oncology, Public Health, Clinical Genetics, TechMed Centre, and Health Technology & Services Research

Subjects
0301 basic medicine, Oncology, Multifactorial Inheritance, PROGNOSIS, Receptor, ErbB-2, LOCI, Gene Expression, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, ErbB-2, Neoplasms, Receptors, Genetics (clinical), Progesterone, Cancer, Genetics & Heredity, Genome, Manchester Cancer Research Centre, Confounding, Hazard ratio, 1184 Genetics, developmental biology, physiology, Neoplasms, Second Primary, Biological Sciences, Middle Aged, Prognosis, Primary tumor, Neoadjuvant Therapy, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Second Primary, 030220 oncology & carcinogenesis, contralateral breast cancer, kConFab Investigators, epidemiology, Female, Risk assessment, Receptors, Progesterone, Life Sciences & Biomedicine, Cohort study, Receptor, Human, Adult, medicine.medical_specialty, ABCTB Investigators, Breast Neoplasms, Risk Assessment, White People, Article, NBCS Collaborators, 03 medical and health sciences, Breast cancer, AGE, SDG 3 - Good Health and Well-being, Asian People, Internal medicine, Breast Cancer, parasitic diseases, Genetics, medicine, Adjuvant therapy, Humans, Genetic Predisposition to Disease, Aged, Proportional Hazards Models, Science & Technology, business.industry, Proportional hazards model, Genome, Human, ResearchInstitutes_Networks_Beacons/mcrc, Prevention, 22/2 OA procedure, Estrogen Receptor alpha, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, polygenic risk score, genetic, business, Genome-Wide Association Study
Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:107 issue:5 pages:837-848 ispartof: location:United States status: published

Published
2020

10. Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Author

Liu, Jingjing, Prager-van der Smissen, Wendy JC, Collée, J Margriet, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Ahearn, Thomas U, Aittomäki, Kristiina, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bernstein, Leslie, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Cai, Hui, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Christiaens, Melissa, Clarke, Christine L, NBCS Collaborators, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harrington, Patricia A, Hart, Steven N, Hartman, Mikael, Hillemanns, Peter, Hopper, John L, Hou, Ming-Feng, Hunter, David J, Huo, Dezheng, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, and Mariapun, Shivaani

Subjects
Homeodomain Proteins, Aging, screening and diagnosis, Genotyping Techniques, Prevention, ABCTB Investigators, Breast Neoplasms, Middle Aged, 4.1 Discovery and preclinical testing of markers and technologies, NBCS Collaborators, Detection, Risk Factors, Clinical Research, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Aetiology, skin and connective tissue diseases, Germ-Line Mutation, Cancer
Abstract

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

Published
2020

11. Two truncating variants in FANCC and breast cancer risk

Author

Dork, T., Peterlongo, P., Mannermaa, A., Bolla, M.K., Wang, Q., Dennis, J., Ahearn, T., Andrulis, I.L., Anton-Culver, H., Arndt, V., Aronson, K.J., Augustinsson, A., Freeman, L.E.B., Beckmann, M.W., Beeghly-Fadiel, A., Behrens, S., Bermisheva, M., Blomqvist, C., Bogdanova, N., Bojesen, S.E., Brauch, H., Brenner, H., Burwinkel, B., Canzian, F., Chan, T.L., Chang-Claude, J., Chanock, S.J., Choi, J.Y., Christiansen, H., Clarke, C.L., Couch, F.J., Czene, K., Daly, M.B., dos-Santos-Silva, I., Dwek, M., Eccles, D.M., Ekici, A.B., Eriksson, M., Evans, D.G., Fasching, P.A., Figueroa, J., Flyger, H., Fritschisl, L., Gabrielson, M., Gago-Dominguez, M., Gao, C., Gapstur, S.M., Garcia-Closas, M., Garcia-Saenz, J.A., Gaudet, M.M., Giles, G.G., Goldberg, M.S., Goldgar, D.E., Guenel, P., Haeberle, L., Haiman, C.A., Hakansson, N., Hall, P., Hamann, U., Hartman, M., Hauke, J., Hein, A., Hillemanns, P., Hogervorst, F.B.L., Hooning, M.J., Hopper, J.L., Howell, T., Huo, D.Z., Ito, H., Iwasaki, M., Jakubowska, A., Janni, W., John, E.M., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Khusnutdinova, E., Kim, S.W., Kitahara, C.M., Koutros, S., Kraft, P., Kristensen, V.N., Kwon, A., Lambrechts, D., Marchand, L. le, Li, J.M., Lindstrom, S., Linet, M., W.Y. lo, Long, J.R., Lophatananon, A., Lubinski, J., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, E., Matsuo, K., Mavroudis, D., Meindl, A., Menon, U., Milne, R.L., Taib, N.A.M., Muir, K., Mulligan, A.M., Neuhausen, S.L., Nevanlinna, H., Neven, P., Newman, W.G., Offit, K., Olopade, O.I., Olshan, A.F., Olson, J.E., Olsson, H., Park, S.K., Park-Simon, T.W., Peto, J., Plaseska-Karanfilska, D., Pohl-Rescigno, E., Presneau, N., Rack, B., Radice, P., Rashid, M.U., Rennert, G., Rennert, H.S., Romero, A., Ruebner, M., Saloustros, E., Schmidt, M.K., Schmutzler, R.K., Schneider, M.O., Schoemaker, M.J., Scott, C., Shen, C.Y., Shu, X.O., Simard, J., Slager, S., Smichkoska, S., Southey, M.C., Spinelli, J.J., Stone, J., Surowy, H., Swerdlow, A.J., Tamimi, R.M., Tapper, W.J., Teo, S.H., Terry, M.B., Toland, A.E., Tollenaar, R.A.E.M., Torres, D., Torres-Mejia, G., Troester, M.A., Truong, T., Tsugane, S., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Veen, E.M. van, Vijai, J., Wendt, C., Wolk, A., Yu, J.C., Zheng, W., Ziogas, A., Ziv, E., Dunning, A.M., Pharoah, P.D.P., Schindler, D., Devilee, P., Easton, D.F., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C.S., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Borresen-Dale, A.L., Alnaes, G.I.G., Sahlberg, K.K., Ottestad, L., Karesen, R., Schlichting, E., Holmen, M.M., Sauer, T., Haakensen, V., Engebraten, O., Naume, B., Fossa, A., Kiserud, C.E., Reinertsen, K.V., Helland, A., Riis, M., Geisler, J., ABCTB Investigators, NBCS Collaborators, Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Dwek, Miriam [0000-0001-7184-2932], Ekici, Arif B [0000-0001-6099-7066], Fasching, Peter A [0000-0003-4885-8471], Figueroa, Jonine [0000-0002-5100-623X], Hein, Alexander [0000-0003-2601-3398], Ito, Hidemi [0000-0002-8023-4581], Matsuo, Keitaro [0000-0003-1761-6314], Menon, Usha [0000-0003-3708-1732], Milne, Roger L [0000-0001-5764-7268], Muir, Kenneth [0000-0001-6429-988X], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G [0000-0002-6382-4678], Peto, Julian [0000-0002-1685-8912], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Schmidt, Marjanka K [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Truong, Thérèse [0000-0002-2943-6786], Tsugane, Shoichiro [0000-0003-4105-2774], Ziogas, Argyrios [0000-0003-4529-3727], Dunning, Alison M [0000-0001-6651-7166], Pharoah, Paul DP [0000-0001-8494-732X], Devilee, Peter [0000-0002-8023-2009], Easton, Douglas F [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Andrulis, Irene L. [0000-0002-4226-6435], Ekici, Arif B. [0000-0001-6099-7066], Fasching, Peter A. [0000-0003-4885-8471], Milne, Roger L. [0000-0001-5764-7268], Newman, William G. [0000-0002-6382-4678], Schmidt, Marjanka K. [0000-0002-2228-429X], Dunning, Alison M. [0000-0001-6651-7166], Pharoah, Paul D. P. [0000-0001-8494-732X], Easton, Douglas F. [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Clinicum, University Management, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Medical Oncology, and Clinical Genetics

Subjects
0301 basic medicine, Oncology, PROTEIN, lcsh:Medicine, 45/47, 0302 clinical medicine, Fanconi anemia, Genotype, lcsh:Science, Sequence Deletion, Multidisciplinary, BRCA1 Protein, Fanconi Anemia Complementation Group C Protein, 1184 Genetics, developmental biology, physiology, BRCA2 Protein, 3. Good health, BIALLELIC MUTATIONS, DNA-REPAIR, Female, 692/499, Medical Genetics, medicine.medical_specialty, PALB2, 3122 Cancers, ABCTB Investigators, Breast Neoplasms, FANCONIS ANEMIA, Article, 692/4028, NBCS Collaborators, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, NONSENSE MUTATION, Genetic Predisposition to Disease, Medicinsk genetik, 45, business.industry, Genetic heterogeneity, lcsh:R, Case-control study, Genetic Variation, Odds ratio, medicine.disease, GENE, Fanconi Anemia, 030104 developmental biology, Risk factors, Case-Control Studies, lcsh:Q, 3111 Biomedicine, business, 030217 neurology & neurosurgery
Abstract

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Published
2019

12. 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

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

Author

Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, and Huang, Guanmengqian

Subjects
Risk, kConFab/AOCS Investigators, Gene Expression, Breast Neoplasms, Medical and Health Sciences, NBCS Collaborators, Clinical Research, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Aetiology, Cancer, screening and diagnosis, Prevention, Human Genome, Single Nucleotide, Biological Sciences, 4.1 Discovery and preclinical testing of markers and technologies, Detection, Case-Control Studies, Female, Transcriptome, Genome-Wide Association Study, Biotechnology, Developmental Biology
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

Published
2018

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

Author

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

Subjects
risk haplotype, familial breast cancer, kConFab/AOCS Investigators, Oncology and Carcinogenesis, linkage analysis, sequencing, NBCS Collaborators
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
2017

15. Association analysis identifies 65 new breast cancer risk loci

Author

Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Published
2017

16. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Author

Ghoussaini, Maya, French, Juliet D, Michailidou, Kyriaki, Nord, Silje, Beesley, Jonathan, Canisus, Sander, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Milne, Roger L, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Alonso, M Rosario, Pita, Guillermo, Neuhausen, Susan L, Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Tessier, Daniel C, Vincent, Daniel, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, kConFab/AOCS Investigators, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Barile, Monica, Couch, Fergus J, Hallberg, Emily, Giles, Graham G, Haiman, Christopher A, Le Marchand, Loic, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Borresen-Dale, Anne-Lise, NBCS Collaborators, Zheng, Wei, Cai, Qiuyin, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Devilee, Peter, Tollenaar, Rob AEM, García-Closas, Montserrat, Figueroa, Jonine, Hall, Per, Czene, Kamila, Brand, Judith S, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J, Koppert, Linetta B, Li, Jingmei, Shu, Xiao-Ou, Zheng, Ying, Cox, Angela, Cross, Simon S, Shah, Mitul, and Rhenius, Valerie

Subjects
Fibroblast Growth Factor, Enhancer Elements, kConFab/AOCS Investigators, Quantitative Trait Loci, Breast Neoplasms, Medical and Health Sciences, Chromosomes, NBCS Collaborators, Cell Line, Promoter Regions, Genetic, Receptors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Cancer, Genetics & Heredity, Tumor, Prevention, Human Genome, Single Nucleotide, Biological Sciences, Estrogen, Haplotypes, Case-Control Studies, Pair 5, Fibroblast Growth Factor 10, Type 2, Human, Receptor
Abstract

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35× 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44× 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12× 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Published
2016

17. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF

Subjects
ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

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