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1,041 results on '"Blomqvist A"'

1. Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

Author: Lopes Cardozo, Josephine MN, Andrulis, Irene L, Bojesen, Stig E, Dörk, Thilo, Eccles, Diana M, Fasching, Peter A, Hooning, Maartje J, Keeman, Renske, Nevanlinna, Heli, Rutgers, Emiel JT, Easton, Douglas F, Hall, Per, Pharoah, Paul DP, van 't Veer, Laura J, Schmidt, Marjanka K, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bolla, Manjeet K, Bonanni, Bernardo, Boyle, Terry, Brenner, Hermann, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Camp, Nicola J, Canzian, Federico, Cardoso, Fatima, Castelao, Jose E, Cessna, Melissa H, Chan, Tsun L, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Colonna, Sarah V, Copson, Ellen, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Drukker, Caroline A, Dunning, Alison M, Dwek, Miriam, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hein, Alexander, Ho, Weang-Kee, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ito, Hidemi, Jakubowska, Anna, Jernström, Helena, John, Esther M, Johnson, Nichola, Jones, Michael E, Joseph, Vijai, Kaaks, Rudolf, Kang, Daehee, Kim, Sung-Won, Kitahara, Cari M, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, and Koutros, Stella
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Good Health and Well Being, Female, Humans, Breast Neoplasms, Risk Factors, Prognosis, Proportional Hazards Models, Breast, Breast Cancer Association Consortium and MINDACT Collaborators, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.
Published: 2023

2. 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, Colonna, Sarah V, 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, 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, Kwong, Ava, Lacey, James V, Lambrechts, Diether, and Le Marchand, Loic
Subjects: Breast Cancer, Genetics, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Black People, Genetic Testing, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Formins, Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Clinical Sciences
Abstract: BackgroundLow-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.MethodsWe 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.ResultsIn European ancestry samples, 14 genes were significantly associated (q
Published: 2023

3. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Lewis, Sarah J, Martin, Richard M, English, Dallas R, Boyle, Terry, Giles, Graham G, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Investigators, ABCTB, Ahearn, Thomas U, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Cessna, Melissa H, Chang-Claude, Jenny, Chanock, Stephen J, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Goldberg, Mark S, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Häberle, Lothar, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Harvie, Michelle, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Hopper, John, Howell, Anthony, Hunter, David J, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, and Manoochehri, Mehdi
Subjects: Aging, Genetics, Breast Cancer, Clinical Research, Cancer, Prevention, Female, Humans, Breast Neoplasms, Exercise, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Sedentary Behavior, Breast Cancer Association Consortium, Breast, Physical activity, Sedentary Behaviour, Engineering, Medical and Health Sciences, Education, Sport Sciences
Abstract: ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
Published: 2022

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

Author: Grootes, Isabelle, Keeman, Renske, Blows, Fiona M, Milne, Roger L, Giles, Graham G, Swerdlow, Anthony J, Fasching, Peter A, Abubakar, Mustapha, Andrulis, Irene L, Anton-Culver, Hoda, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Briceno, Ignacio, Burwinkel, Barbara, Camp, Nicola J, Castelao, Jose E, Choi, Ji-Yeob, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Ernst, Kristina, Evans, D Gareth, Figueroa, Jonine D, Fink, Visnja, Floris, Giuseppe, Fox, Stephen, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Sáenz, José A, González-Neira, Anna, Haeberle, Lothar, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartman, Mikael, Hein, Alexander, Hooning, Maartje J, Hou, Ming-Feng, Howell, Sacha J, Investigators, ABCTB, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Li, Jingmei, Lubiński, Jan, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Taib, Nur Aishah Mohd, Mulligan, Anna Marie, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Osorio, Ana, Park, Sue K, Park-Simon, Tjoung-Won, Patel, Alpa V, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rennert, Gad, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor J, Schneeweiss, Andreas, Schochter, Fabienne, Schoemaker, Minouk J, Shen, Chen-Yang, Shibli, Rana, Sinn, Peter, Tapper, William J, Tawfiq, Essa, Teo, Soo Hwang, Teras, Lauren R, Torres, Diana, Vachon, Celine M, van Deurzen, Carolien HM, Wendt, Camilla, and Williams, Justin A
Subjects: Cancer, Breast Cancer, Breast Neoplasms, Female, Humans, Progesterone, Prognosis, Receptor, ErbB-2, Receptors, Progesterone, PREDICT Breast, breast cancer, Progesterone receptor, ABCTB Investigators, kConFab Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundPredict 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).MethodThe 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.ResultsHaving 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 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.ConclusionThe 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 predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
Published: 2022

5. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

Author: Giardiello, Daniele, Hooning, Maartje J, Hauptmann, Michael, Keeman, Renske, Heemskerk-Gerritsen, BAM, Becher, Heiko, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Camp, Nicola J, Czene, Kamila, Devilee, Peter, Eccles, Diana M, Fasching, Peter A, Figueroa, Jonine D, Flyger, Henrik, García-Closas, Montserrat, Haiman, Christopher A, Hamann, Ute, Hopper, John L, Jakubowska, Anna, Leeuwen, Floor E, Lindblom, Annika, Lubiński, Jan, Margolin, Sara, Martinez, Maria Elena, Nevanlinna, Heli, Nevelsteen, Ines, Pelders, Saskia, Pharoah, Paul DP, Siesling, Sabine, Southey, Melissa C, van der Hout, Annemieke H, van Hest, Liselotte P, Chang-Claude, Jenny, Hall, Per, Easton, Douglas F, Steyerberg, Ewout W, and Schmidt, Marjanka K
Subjects: Genetics, Breast Cancer, Prevention, Cancer, Humans, Female, Breast Neoplasms, Mastectomy, Prophylactic Mastectomy, Germ-Line Mutation, Risk Factors, Contralateral breast cancer, Risk prediction, Contralateral preventive mastectomy, Clinical decision-making, Breast cancer genetic predisposition, Breast Cancer Association Consortium, BCAC, Prediction performance, BRCA1/2 germline mutation, Polygenic risk score, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundPrediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors.MethodsWe included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models.ResultsThe discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsAdditional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
Published: 2022

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

Author: Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, and McLean, Catriona
Subjects: Human Genome, Cancer, Genetics, Clinical Research, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Female, Genome-Wide Association Study, Humans, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Risk, Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundGenome-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.MethodsAmong 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.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate
Published: 2022

7. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association ConsortiumBreast Cancer Risk Factors and Survival By Tumor Subtype

Author: Morra, Anna, Jung, Audrey Y, Behrens, Sabine, Keeman, Renske, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi K, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Briceno, Ignacio, Brucker, Sara Y, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Choi, Ji-Yeob, Clarke, Christine L, Investigators, for the ABCTB, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Egan, Kathleen M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny N, Hart, Steven N, Hartman, Mikael, Heyworth, Jane S, Hoppe, Reiner, Hopper, John L, Hunter, David J, Ito, Hidemi, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Collaborators, for the NBCS, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mariapun, Shivaani, Matsuo, Keitaro, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Newman, William G, Noh, Dong-Young, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Petridis, Christos, Pharoah, Paul DP, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, and Rhenius, Valerie
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Aging, Estrogen, Cancer, Prevention, Breast Cancer, Good Health and Well Being, Adult, Aged, Breast Neoplasms, Cause of Death, Female, Humans, Life Style, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Prospective Studies, Risk Factors, Survival Analysis, ABCTB Investigators, NBCS Collaborators, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundIt is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.MethodsWe analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.ResultsThere was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus 0-
Published: 2021

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

Author: Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, and Hopper, John L
Subjects: GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Linkage Disequilibrium, Mutation, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Adult, Middle Aged, Female, Genome-Wide Association Study, Breast Cancer, Prevention, Cancer, Genetic Testing, Human Genome, Genetics, 2.1 Biological and endogenous factors
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P
Published: 2021

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

10. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Author: Dorling, Leila, Carvalho, Sara, Allen, Jamie, González-Neira, Anna, Luccarini, Craig, Wahlström, Cecilia, Pooley, Karen A, Parsons, Michael T, Fortuno, Cristina, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Keeman, Renske, Alonso, M Rosario, Álvarez, Nuria, Herraez, Belen, Fernandez, Victoria, Núñez-Torres, Rocio, Osorio, Ana, Valcich, Jeanette, Li, Minerva, Törngren, Therese, Harrington, Patricia A, Baynes, Caroline, Conroy, Don M, Decker, Brennan, Fachal, Laura, Mavaddat, Nasim, Ahearn, Thomas, Aittomäki, Kristiina, Antonenkova, Natalia N, Arnold, Norbert, Arveux, Patrick, Ausems, Margreet GEM, Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Briceno, Ignacio, Brüning, Thomas, Burwinkel, Barbara, Cameron, David A, Camp, Nicola J, Campbell, Archie, Carracedo, Angel, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, Christiansen, Hans, Collée, J Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Czene, Kamila, Dörk, Thilo, Ekici, Arif B, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Försti, Asta, Gabrielson, Marike, Gago-Dominguez, Manuela, Georgoulias, Vassilios, Gil, Fabian, Giles, Graham G, Glendon, Gord, Garcia, Encarna B Gómez, Alnæs, Grethe I Grenaker, Guénel, Pascal, Hadjisavvas, Andreas, Haeberle, Lothar, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Ho, Weang Kee, Hooning, Maartje J, Howell, Anthony, Humphreys, Keith, Idris, Faiza, Jakubowska, Anna, and Jung, Audrey
Subjects: Breast Cancer, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Logistic Models, Middle Aged, Mutation, Missense, Odds Ratio, Risk, Sequence Analysis, DNA, Young Adult, Breast Cancer Association Consortium, Medical and Health Sciences, General & Internal Medicine
Abstract: BackgroundGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.MethodsWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.ResultsProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.ConclusionsThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).
Published: 2021

11. Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status

Author: Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu‐full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton‐Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang‐Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Collaborators, GEMO Study, Collaborators, EMBRACE, Collaborators, GC‐HBOC study, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, dos‐Santos‐Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García‐Closas, Montserrat, García‐Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González‐Neira, Anna, and Greene, Mark H
Subjects: Biological Sciences, Health Sciences, Genetics, Cancer, Biotechnology, Prevention, Clinical Research, Human Genome, Estrogen, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Estrogens, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Receptors, Estrogen, Risk Assessment, Transcriptome, Vesicular Transport Proteins, breast cancer subtype, causal gene, GWAS, TWAS, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Public Health and Health Services, Epidemiology
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
Published: 2020

12. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author: Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, and Hillemanns, Peter
Subjects: kConFab Investigators, ABCTB Investigators, EMBRACE Study, GEMO Study Collaborators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Case-Control Studies, Linkage Disequilibrium, Mutation, Female, Genome-Wide Association Study, Triple Negative Breast Neoplasms, Human Genome, Cancer, Prevention, Genetics, Breast Cancer, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

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

Author: Escala-Garcia, Maria, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Ashworth, Alan, Auer, Paul L, Auvinen, Päivi, Beckmann, Matthias W, Beesley, Jonathan, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Dwek, Miriam, Earl, Helena M, Eccles, Diana M, Eliassen, A Heather, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Guo, Qi, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Harrington, Patricia A, Hiller, Louise, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Chiun-Sheng, Huang, Guanmengqian, Hunter, David J, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Kitahara, Cari M, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, and Olsson, Håkan
Subjects: Germ Cells, Humans, Breast Neoplasms, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Receptors, Estrogen, Prognosis, Computational Biology, Signal Transduction, Apoptosis, Genotype, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Circadian Clocks, Gq-G11, Receptors, Estrogen, Cancer, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
Published: 2020

14. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author: Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Allen, Jamie, Kar, Siddhartha, Pooley, Karen A, Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P, Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auber, Bernd, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Camp, Nicola J, Campbell, Ian, Canzian, Federico, Carroll, Jason S, Carter, Brian D, Castelao, Jose E, Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Floris, Giuseppe, and Flyger, Henrik
Subjects: GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Bayes Theorem, Risk Factors, Chromosome Mapping, Regulatory Sequences, Nucleic Acid, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Female, Genome-Wide Association Study, Biomarkers, Tumor, Genetic Testing, Prevention, Genetics, Cancer, Breast Cancer, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Published: 2020

15. Two truncating variants in FANCC and breast cancer risk.

Author: Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans BL, Hooning, Maartje J, Hopper, John L, Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindström, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, and Meindl, Alfons
Subjects: ABCTB Investigators, NBCS Collaborators, Humans, Breast Neoplasms, Fanconi Anemia, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Case-Control Studies, Sequence Deletion, Female, Fanconi Anemia Complementation Group C Protein, Genetic Variation, Clinical Research, Breast Cancer, Genetics, Cancer, 2.1 Biological and endogenous factors, Biochemistry and Cell Biology, Other Physical Sciences
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

16. Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

Author: Shu, Xiang, Wu, Lang, Khankari, Nikhil K, Shu, Xiao-Ou, Wang, Thomas J, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Pharoah, Paul DP, Andrulis, Irene L, Hunter, David J, Simard, Jacques, Easton, Douglas F, Zheng, Wei, Alicia, Beeghly-Fadiel J, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beane Freeman, Laura E, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, David Cheng, Ting-Yuan, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Dwek, Miriam, Earp, H Shelton, Eccles, Diana M, Heather Eliassen, A, Engel, Christoph, Eriksson, Mikael, Gareth Evans, D, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, 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, He, Wei, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hogervorst, Frans B, Hollestelle, Antoinette, and Hoover, Robert N
Subjects: Clinical Research, Diabetes, Prevention, Nutrition, Obesity, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Blood Glucose, Body Mass Index, Breast Neoplasms, Diabetes Mellitus, Type 2, Female, Humans, Insulin, Mendelian Randomization Analysis, Middle Aged, Obesity, Abdominal, Waist-Hip Ratio, Breast cancer, insulin, glucose, obesity, genetics, Mendelian randomization analysis, Breast Cancer Association Consortium, Statistics, Public Health and Health Services, Epidemiology
Abstract: BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 × 10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 × 10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 × 10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 × 10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
Published: 2019

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

Author: Ferreira, Manuel A, Gamazon, Eric R, Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, and BCFR Investigators
Subjects: EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Gene Expression Profiling, Quantitative Trait Loci, Female, Genome-Wide Association Study, Prevention, Cancer, Human Genome, Aging, Breast Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Published: 2019

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

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, and Holleczek, Bernd
Subjects: NBCS Collaborators, Chromosomes, Human, Pair 7, Humans, Breast Neoplasms, Receptors, Estrogen, Prognosis, Proportional Hazards Models, Bayes Theorem, Female, Genetic Variation, Genome-Wide Association Study, White People, Genetics, Breast Cancer, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-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).ResultsWe did not find any variant associated with breast cancer-specific mortality at P
Published: 2019

19. Shared heritability and functional enrichment across six solid cancers.

Author: Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, deFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, and Ganz, Patricia A
Subjects: Humans, Breast Neoplasms, Colorectal Neoplasms, Ovarian Neoplasms, Head and Neck Neoplasms, Lung Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Neoplasm Proteins, Case-Control Studies, Smoking, Mental Disorders, Inheritance Patterns, Phenotype, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Prevention, Cancer, Breast Cancer, Genetics, Rare Diseases, Lung Cancer, Human Genome, Colo-Rectal Cancer, Digestive Diseases, Lung, MD Multidisciplinary
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Published: 2019

20. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Author: Mavaddat, Nasim, Michailidou, Kyriaki, Dennis, Joe, Lush, Michael, Fachal, Laura, Lee, Andrew, Tyrer, Jonathan P, Chen, Ting-Huei, Wang, Qin, Bolla, Manjeet K, Yang, Xin, Adank, Muriel A, Ahearn, Thomas, Aittomäki, Kristiina, Allen, Jamie, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Auvinen, Päivi, Barrdahl, Myrto, Beane Freeman, Laura E, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Brenner, Hermann, Brentnall, Adam, Brock, Ian W, Brooks-Wilson, Angela, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chlebowski, Rowan, Christiansen, Hans, Clarke, Christine L, Collée, J Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Försti, Asta, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Georgoulias, Vassilios, Giles, Graham G, Gilyazova, Irina R, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grenaker Alnæs, Grethe I, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, and Hankinson, Susan E
Subjects: ABCTB Investigators, kConFab/AOCS Investigators, NBCS Collaborators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Receptors, Estrogen, Medical History Taking, Risk Assessment, Reproducibility of Results, Age Factors, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, breast, cancer, epidemiology, genetic, polygenic, prediction, risk, score, screening, stratification, Human Genome, Cancer, Genetics, Clinical Research, Prevention, Breast Cancer, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Published: 2019

21. 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: Biological Sciences, Genetics, Human Genome, Biotechnology, Prevention, Breast Cancer, Women's Health, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, Generic health relevance, Breast Neoplasms, Case-Control Studies, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk, Transcriptome, NBCS Collaborators, kConFab/AOCS Investigators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational 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

22. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author: Milne, Roger L, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K, McGuffog, Lesley, Wang, Qin, Aalfs, Cora M, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B, Amos, Christopher I, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L, Ausems, Margreet GEM, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B, Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves-Jean, Blazer, Kathleen R, Blok, Marinus J, Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Bozsik, Aniko, Bradbury, Angela R, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Bressac-de Paillerets, Brigitte, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byun, Jinyoung, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D, Castelao, J Esteban, Castera, Laurent, Caux-Moncoutier, Virginie, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Xiaoqing, Cheng, Ting-Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen BM, Clarke, Christine L, Conner, Thomas, Conroy, Don M, and Cook, Jackie
Subjects: Biological Sciences, Genetics, Cancer, Human Genome, Prevention, Breast Cancer, Aging, Estrogen, 2.1 Biological and endogenous factors, Aetiology, BRCA1 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab/AOCS Investigators, NBSC Collaborators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Published: 2017

23. Association analysis identifies 65 new breast cancer risk loci

Author: Michailidou, Kyriaki, Lindström, Sara, Dennis, Joe, Beesley, Jonathan, Hui, Shirley, Kar, Siddhartha, Lemaçon, Audrey, Soucy, Penny, Glubb, Dylan, Rostamianfar, Asha, Bolla, Manjeet K, Wang, Qin, Tyrer, Jonathan, Dicks, Ed, Lee, Andrew, Wang, Zhaoming, Allen, Jamie, Keeman, Renske, Eilber, Ursula, French, Juliet D, Qing Chen, Xiao, Fachal, Laura, McCue, Karen, McCart Reed, Amy E, Ghoussaini, Maya, Carroll, Jason S, Jiang, Xia, Finucane, Hilary, Adams, Marcia, Adank, Muriel A, Ahsan, Habibul, Aittomäki, Kristiina, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Arun, Banu, Auer, Paul L, Bacot, François, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Butterbach, Katja, Cai, Qiuyin, Cai, Hui, Caldés, Trinidad, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chan, Tsun L, David Cheng, Ting-Yuan, Seng Chia, Kee, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Collée, Margriet, Conroy, Don M, Cordina-Duverger, Emilie, Cornelissen, Sten, Cox, David G, 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, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Elvira, Mingajeva, and Engel, Christoph
Subjects: Cancer, Asia, Asian People, Binding Sites, Breast Neoplasms, Computer Simulation, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors, White People, NBCS Collaborators, ABCTB Investigators, ConFab/AOCS Investigators, General Science & Technology
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

24. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Author: Muranen, Taru A, Greco, Dario, Blomqvist, Carl, Aittomäki, Kristiina, Khan, Sofia, Hogervorst, Frans, Verhoef, Senno, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Luben, Robert, Bojesen, Stig E, Nordestgaard, Børge G, Schoemaker, Minouk, Swerdlow, Anthony, García-Closas, Montserrat, Figueroa, Jonine, Dörk, Thilo, Bogdanova, Natalia V, Hall, Per, Li, Jingmei, Khusnutdinova, Elza, Bermisheva, Marina, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Investigators, NBCS, Peto, Julian, dos Santos Silva, Isabel, Couch, Fergus J, Olson, Janet E, Hillemans, Peter, Park-Simon, Tjoung-Won, Brauch, Hiltrud, Hamann, Ute, Burwinkel, Barbara, Marme, Frederik, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Cross, Simon S, Sawyer, Elinor J, Tomlinson, Ian, Lambrechts, Diether, Moisse, Matthieu, Lindblom, Annika, Margolin, Sara, Hollestelle, Antoinette, Martens, John WM, Fasching, Peter A, Beckmann, Matthias W, Andrulis, Irene L, Knight, Julia A, Investigators, kConFab AOCS, Anton-Culver, Hoda, Ziogas, Argyrios, Giles, Graham G, Milne, Roger L, Brenner, Hermann, Arndt, Volker, Mannermaa, Arto, Kosma, Veli-Matti, Chang-Claude, Jenny, Rudolph, Anja, Devilee, Peter, Seynaeve, Caroline, Hopper, John L, Southey, Melissa C, John, Esther M, Whittemore, Alice S, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Easton, Douglas F, Schmidt, Marjanka K, and Nevanlinna, Heli
Subjects: Cancer, Prevention, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Checkpoint Kinase 2, Female, Genes, Modifier, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Sequence Deletion, breast cancer, Breast Cancer Association Consortium, CHEK2*1100delC, common variants, polygenic risk score, NBCS Investigators, kConFab/AOCS Investigators, Genetics, Clinical Sciences, Genetics & Heredity
Abstract: PurposeCHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).MethodsUsing genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.ResultsThe PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.ConclusionOur results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
Published: 2017

25. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Author: Hamdi, Yosr, Soucy, Penny, Adoue, Véronique, Michailidou, Kyriaki, Canisius, Sander, Lemaçon, Audrey, Droit, Arnaud, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Baynes, Caroline, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Chang-Claude, Jenny, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, García-Closas, Montserrat, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Grenaker-Alnæs, Grethe, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Hamann, Ute, Hallberg, Emily, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jones, Michael, Kabisch, Maria, Kataja, Vesa, Lambrechts, Diether, Marchand, Loic Le, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Maranian, Mel, Margolin, Sara, Marme, Frederik, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olswold, Curtis, Peto, Julian, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Radice, Paolo, Rudolph, Anja, Sawyer, Elinor J, Schmidt, Marjanka K, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Vachon, Celine, Van Den Ouweland, Ans MW, Wang, Qin, Winqvist, Robert, Investigators, kConFab AOCS, Zheng, Wei, Benitez, Javier, Chenevix-Trench, Georgia, Dunning, Alison M, Pharoah, Paul DP, Kristensen, Vessela, Hall, Per, Easton, Douglas F, Pastinen, Tomi, Nord, Silje, and Simard, Jacques
Subjects: Human Genome, Cancer, Breast Cancer, Prevention, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Canada, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 4, DNA Helicases, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Mitochondrial Proteins, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Assessment, Risk Factors, breast cancer, genetic susceptibility, association studies, differential allelic expression, cis-regulatory variants, NBCS Collaborators, kConFab/AOCS Investigators, Oncology and Carcinogenesis
Abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
Published: 2016

26. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen BM, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, and Zheng, Wei
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Aging, Breast Cancer, Cancer, Women's Health, Rare Diseases, Prevention, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Fanconi Anemia Complementation Group N Protein, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mutation, Nuclear Proteins, Ovarian Neoplasms, Prostatic Neoplasms, Risk, Tumor Suppressor Proteins, Australian Ovarian Cancer Study Group, Cancer: breast, Cancer: ovary, Cancer: prostate, cancer predisposition, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundThe rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.MethodsWe genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.ResultsFor European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.ConclusionsThis report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

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

Author: Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline, Michailidou, Kyriaki, Tyrer, Jonathan, Beesley, Jonathan, Ramus, Susan J, Li, Qiyuan, Delgado, Melissa K, Lee, Janet M, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K, Arver, Brita, Bandera, Elisa V, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Benitez, Javier, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Blot, William, Bogdanova, Natalia, Bojesen, Anders, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Bruinsma, Fiona, Brunet, Joan, Buhari, Shaik Ahmad, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S, Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji-Yeob, Claes, Kathleen BM, GEMO Study Collaborators, Cook, Linda S, Cox, Angela, Cramer, Daniel W, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Diez, Orland, Doherty, Jennifer A, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, Dumont, Martine, Ehrencrona, Hans, Ejlertsen, Bent, Ellis, Steve, EMBRACE, Engel, Christoph, Lee, Eunjung, Evans, D Gareth, Fasching, Peter A, Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D, Fridley, Brooke L, Friedman, Eitan, Frost, Debra, Gambino, Gaetana, Ganz, Patricia A, Garber, Judy, García-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Ghoussaini, Maya, Giles, Graham G, Glasspool, Rosalind, Godwin, Andrew K, Goldberg, Mark S, and Goldgar, David E
Subjects: GEMO Study Collaborators, EMBRACE, Hereditary Breast and Ovarian Cancer Research Group Netherlands, KConFab Investigators, Australian Ovarian Cancer Study Group, Chromosomes, Human, Pair 19, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, RNA, Messenger, Genotype, Polymorphism, Single Nucleotide, Alleles, African Continental Ancestry Group, Asian Continental Ancestry Group, Female, Genome-Wide Association Study, Chromosomes, Human, Pair 19, RNA, Messenger, Polymorphism, Single Nucleotide, Prevention, Breast Cancer, Ovarian Cancer, Cancer, Rare Diseases, Genetics, 2.1 Biological and endogenous factors
Abstract: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P
Published: 2016

28. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Kar, Siddhartha P, Beesley, Jonathan, Olama, Ali Amin Al, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, Investigators, ABCTB, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, Study, AOCS Study Group amp Australian Cancer, BioResource, APCB, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Aging, Urologic Diseases, Prostate Cancer, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Signal Transduction, ABCTB Investigators, AOCS Study Group & Australian Cancer Study, APCB BioResource, kConFab Investigators, NBCS Investigators, GENICA Network, PRACTICAL consortium, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract: UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
Published: 2016

29. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Author: Arndt, Volker, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham, Guénel, Pascal, Haiman, Christopher, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje, Hopper, John, Jakubowska, Anna, Jasmine, Farzana, John, Esther, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan, Nevanlinna, Heli, Neven, Patrick, Olson, Janet, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor, Schmutzler, Rita, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa, Swerdlow, Anthony, Toland, Amanda, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob, Verhoef, Senno, Wang-Gohrke, Shan, Whittemore, Alice, Winqvist, Robert, Pilar Zamora, M, Zhao, Hui, Dunning, Alison, Simard, Jacques, Hall, Per, Kraft, Peter, Pharoah, Paul, Hunter, David, Easton, Douglas, and Zheng, Wei
Subjects: Breast cancer, Epidemiology, GWAS, Genetic susceptibility, Type 2 diabetes, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People
Abstract: PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

30. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

Author: Zhao, Zhiguo, Wen, Wanqing, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Zhang, Ben, Long, Jirong, Shu, Xiao-Ou, Schmidt, Marjanka K, Milne, Roger L, García-Closas, Montserrat, Chang-Claude, Jenny, Lindstrom, Sara, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia V, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, John, Esther M, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia A, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen E, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, and Tomlinson, Ian
Subjects: Genetics, Breast Cancer, Prevention, Diabetes, Aging, Cancer, Clinical Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People, Type 2 diabetes, Genetic susceptibility, GWAS, Breast cancer, Epidemiology, Oncology and Carcinogenesis, Public Health and Health Services
Abstract: PurposeType 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.MethodsWe constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.ResultsThe T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).ConclusionsWe have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

31. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Hollestelle, Antoinette, van der Baan, Frederieke H, Berchuck, Andrew, Johnatty, Sharon E, Aben, Katja K, Agnarsson, Bjarni A, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Antoniou, Antonis C, Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K, Arver, Brita, Ashworth, Alan, Group, Australian Ovarian Cancer Study, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V, Barrowdale, Daniel, Bean, Yukie T, Beckmann, Lars, Beckmann, Matthias W, Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brand, Judith S, Brauch, Hiltrud, Register, Breast Cancer Family, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J, Claes, Kathleen BM, Collée, J Margriet, Cook, Linda S, Couch, Fergus J, Cox, Angela, Cramer, Daniel, Cross, Simon S, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, deFazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M, Diez, Orland, Doherty, Jennifer A, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, Dos Santos Silva, Isabel, du Bois, Andreas, Dumont, Martine, Dunning, Alison M, Duran, Mercedes, Easton, Douglas F, Eccles, Diana, Edwards, Robert P, Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B, Ellis, Steve D, EMBRACE, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Feliubadalo, Lidia, Figueroa, Jonine, and Flesch-Janys, Dieter
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Prevention, Breast Cancer, Clinical Trials and Supportive Activities, Genetic Testing, Ovarian Cancer, Women's Health, Rare Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Proto-Oncogene Proteins p21(ras), KRAS variant, Breast cancer, Ovarian cancer, Genetic association, Clinical outcome, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, Australian Ovarian Cancer Study Group, Breast Cancer Family Register, EMBRACE, GEMO Study Collaborators, GENICA Network, HEBON, KConFab Investigators, SWE-BRCA, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract: ObjectiveClinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.MethodsCentralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).ResultsWe found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.Conclusionsrs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
Published: 2016

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

Author: Couch, Fergus J, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Mendoza-Fandino, Gustavo A, Nord, Silje, Lilyquist, Janna, Olswold, Curtis, Hallberg, Emily, Agata, Simona, Ahsan, Habibul, Aittomäki, Kristiina, Ambrosone, Christine, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K, Arver, Brita, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Lars, Beckmann, Matthias W, Benitez, Javier, Blank, Stephanie V, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Canzian, Federico, Carpenter, Jane, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Damiola, Francesca, Darabi, Hatef, de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan C, Dolcetti, Riccardo, Domchek, Susan M, Dorfling, Cecilia M, Dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Eccles, Diana M, Ehrencrona, Hans, Ekici, Arif B, Eliassen, Heather, Ellis, Steve, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Försti, Asta, Fostira, Florentia, Foulkes, William D, Friebel, Tara, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gammon, Marilie D, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, Gaudet, Mia M, Gayther, Simon A, Gerdes, Anne-Marie, Ghoussaini, Maya, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Gunter, Marc, Haeberle, Lothar, Haiman, Christopher A, Hamann, Ute, Hansen, Thomas VO, Hart, Steven, Healey, Sue, Heikkinen, Tuomas, Henderson, Brian E, and Herzog, Josef
Subjects: Chromosomes, Human, Pair 2, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Cyclophilins, tRNA Methyltransferases, BRCA1 Protein, Receptors, Estrogen, Risk Factors, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Chromosomes, Human, Pair 2, Receptors, Estrogen, Polymorphism, Single Nucleotide, Breast Cancer, Cancer, Prevention, Genetics, Human Genome, 2.1 Biological and endogenous factors
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P
Published: 2016

33. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Author: Dunning, Alison M, Michailidou, Kyriaki, Kuchenbaecker, Karoline B, Thompson, Deborah, French, Juliet D, Beesley, Jonathan, Healey, Catherine S, Kar, Siddhartha, Pooley, Karen A, Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A, Sallari, Richard C, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S, Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Hopper, John L, Southey, Melissa C, Broeks, Annegien, Schmidt, Marjanka K, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Fasching, Peter A, Dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, González-Neira, Anna, Perez, Jose IA, Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Aittomäki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkäs, Katri, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E, Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans MW, Humphreys, Keith, Gao, Yu-Tang, and Shu, Xiao-Ou
Subjects: EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Carrier Proteins, Cell Cycle Proteins, Estrogen Receptor alpha, Risk Factors, Gene Expression, Gene Expression Regulation, Neoplastic, Base Sequence, Protein Binding, Phenotype, Polymorphism, Single Nucleotide, Female, Genetic Association Studies, Cancer, Clinical Research, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Published: 2016

34. RAD51B in Familial Breast Cancer.

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

35. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Author: Zhang, Ben, Shu, Xiao-Ou, Delahanty, Ryan J, Zeng, Chenjie, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Wen, Wanqing, Long, Jirong, Li, Chun, Dunning, Alison M, Chang-Claude, Jenny, Shah, Mitul, Perkins, Barbara J, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Lambrechts, Diether, Neven, Patrick, Wildiers, Hans, Floris, Giuseppe, Schmidt, Marjanka K, Rookus, Matti A, van den Hurk, Katja, de Kort, Wim LAM, Couch, Fergus J, Olson, Janet E, Hallberg, Emily, Vachon, Celine, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Li, Jingmei, Humphreys, Keith, Brand, Judith, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Menegaux, Florence, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Benitez, Javier, Zamora, M Pilar, Perez, Jose IA, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Chenevix-Trench, Georgia, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Marchand, Loic Le, Lindblom, Annika, Margolin, Sara, Hooning, Maartje J, Martens, John WM, Tilanus-Linthorst, Madeleine MA, Collée, J Margriet, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Giles, Graham G, Milne, Roger L, McLean, Catriona, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, and Stegmaier, Christa
Subjects: Clinical Research, Aging, Cancer, Prevention, Breast Cancer, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Body Height, Breast Neoplasms, Evidence-Based Medicine, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Prospective Studies, Risk Factors, kConFab Investigators, Australian Ovarian Study Group, DRIVE Project, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8). Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
Published: 2015

36. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Author: Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, McArdle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Goncalo, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, Caterina, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García-Closas, Montserrat, Giles, Graham G, Girotto, Giorgia G, Goldberg, Mark S, González-Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, and Hamann, Ute
Subjects: PRACTICAL consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study, Hypothalamus, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Genomics, Age Factors, Signal Transduction, DNA Repair, Aging, Reproduction, Menopause, Genotype, Phenotype, Models, Genetic, Adult, Middle Aged, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Models, Genetic, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract: Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Published: 2015

37. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

Author: Orr, Nick, Dudbridge, Frank, Dryden, Nicola, Maguire, Sarah, Novo, Daniela, Perrakis, Eleni, Johnson, Nichola, Ghoussaini, Maya, Hopper, John, Southey, Melissa, Apicella, Carmel, Stone, Jennifer, Schmidt, Marjanka, Broeks, Annegien, Vant Veer, Laura, Hogervorst, Frans, Fasching, Peter, Haeberle, Lothar, Ekici, Arif, Beckmann, Matthias, Gibson, Lorna, Aitken, Zoe, Warren, Helen, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Chistof, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Sanchez, Marie, Bojesen, Stig, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Benitez, Javier, Zamora, Maria, Arias Perez, Jose, Menéndez, Primitiva, Neuhausen, Susan, Brenner, Hermann, Dieffenbach, Aida, Arndt, Volker, Stegmaier, Christa, Hamann, Ute, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, Ko, Yon-Dschun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Bogdanova, Natalia, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana, Chenevix-Trench, Georgia, Beesley, Jonathan, Lambrechts, Diether, Moisse, Matthieu, Floris, Guiseppe, Beuselinck, Benoit, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Peissel, Bernard, Pensotti, Valeria, Couch, Fergus, Olson, Janet, Slettedahl, Seth, Vachon, Celine, Giles, Graham, Milne, Roger, McLean, Catriona, Haiman, Christopher, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark, Labrèche, France, Dumont, Martine, Kristensen, Vessela, Alnæs, Grethe, Nord, Silje, Borresen-Dale, Anne-Lise, Zheng, Wei, and Deming-Halverson, Sandra
Subjects: Adult, Aged, Asian People, Breast Neoplasms, Chromosome Mapping, Chromosomes, Human, Pair 9, Enhancer Elements, Genetic, Estrogen Receptor alpha, Female, GATA3 Transcription Factor, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 3-alpha, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Middle Aged, Polymorphism, Single Nucleotide, Risk, White People
Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
Published: 2015

38. Prediction of breast cancer risk based on profiling with common genetic variants.

Author: Mavaddat, Nasim, Pharoah, Paul, Michailidou, Kyriaki, Tyrer, Jonathan, Brook, Mark, Bolla, Manjeet, Wang, Qin, Dennis, Joe, Dunning, Alison, Shah, Mitul, Luben, Robert, Brown, Judith, Bojesen, Stig, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Peto, Julian, Dos-Santos-Silva, Isabel, Dudbridge, Frank, Johnson, Nichola, Schmidt, Marjanka, Broeks, Annegien, Verhoef, Senno, Rutgers, Emiel, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk, Figueroa, Jonine, Chanock, Stephen, Brinton, Louise, Lissowska, Jolanta, Couch, Fergus, Olson, Janet, Vachon, Celine, Pankratz, Vernon, Lambrechts, Diether, Wildiers, Hans, Van Ongeval, Chantal, van Limbergen, Erik, Kristensen, Vessela, Grenaker Alnæs, Grethe, Nord, Silje, Borresen-Dale, Anne-Lise, Nevanlinna, Heli, Muranen, Taru, Aittomäki, Kristiina, Blomqvist, Carl, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Fasching, Peter, Haeberle, Lothar, Ekici, Arif, Beckmann, Matthias, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Trentham-Dietz, Amy, Newcomb, Polly, Titus, Linda, Egan, Kathleen, Hunter, David, Lindstrom, Sara, Tamimi, Rulla, Kraft, Peter, Rahman, Nazneen, Turnbull, Clare, Renwick, Anthony, Seal, Sheila, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Benitez, Javier, Pilar Zamora, M, Arias Perez, Jose, Menéndez, Primitiva, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Bogdanova, Natalia, Antonenkova, Natalia, Dörk, Thilo, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Bernstein, Leslie, Devilee, Peter, Tollenaar, Robert, Seynaeve, Caroline, van Asperen, Christi, Cox, Angela, Cross, Simon, and Reed, Malcolm
Subjects: Adult, Aged, Biomarkers, Tumor, Breast Neoplasms, Europe, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Predictive Value of Tests, Receptors, Estrogen, Risk Assessment, Risk Factors
Abstract: BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
Published: 2015

39. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

Author: Kabisch, Maria, Bermejo, Justo Lorenzo, Dünnebier, Thomas, Ying, Shibo, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Shah, Mitul, Perkins, Barbara J, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Lambrechts, Diether, Neven, Patrick, Peeters, Stephanie, Weltens, Caroline, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Purrington, Kristen, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, dos-Santos-Silva, Isabel, Johnson, Nichola, Fletcher, Olivia, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Hogervorst, Frans BL, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Burwinkel, Barbara, Marmé, Frederik, Yang, Rongxi, Bugert, Peter, González-Neira, Anna, Benitez, Javier, Zamora, M Pilar, Perez, Jose I Arias, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Haiman, Christopher A, Schumacher, Fredrick, Henderson, Brian E, Le Marchand, Loic, Lindblom, Annika, Margolin, Sara, Hooning, Maartje J, Hollestelle, Antoinette, Kriege, Mieke, Koppert, Linetta B, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Slettedahl, Seth, Toland, Amanda E, Vachon, Celine, Yannoukakos, Drakoulis, Giles, Graham G, Milne, Roger L, McLean, Catriona, Fasching, Peter A, Ruebner, Matthias, Ekici, Arif B, Beckmann, Matthias W, Brenner, Hermann, Dieffenbach, Aida K, Arndt, Volker, Stegmaier, Christa, Ashworth, Alan, Orr, Nicholas, Schoemaker, Minouk J, and Swerdlow, Anthony
Subjects: Cancer, Human Genome, Prevention, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, 3' Untranslated Regions, Aurora Kinase B, Breast Neoplasms, Case-Control Studies, Cell Cycle Proteins, Chromosomal Proteins, Non-Histone, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inhibitor of Apoptosis Proteins, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk, Survivin, White People, kConFab Investigators, Australian Ovarian Cancer Study Group, GENICA Network, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
Published: 2015

40. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Author: Glubb, Dylan M, Maranian, Mel J, Michailidou, Kyriaki, Pooley, Karen A, Meyer, Kerstin B, Kar, Siddhartha, Carlebur, Saskia, O’Reilly, Martin, Betts, Joshua A, Hillman, Kristine M, Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, van der Schoot, C Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Ruebner, Matthias, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul DP, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, González-Neira, Anna, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Anton-Culver, Hoda, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Ko, Yon-Dschun, Brüning, Thomas, Network, The GENICA, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Dörk, Thilo, Bogdanova, Natalia V, Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Investigators, kConFab, Wu, Anna H, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, and Radice, Paolo
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Prevention, Breast Cancer, Cancer, Estrogen, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 5, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, MAP Kinase Kinase Kinase 1, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Racial Groups, Risk Factors, GENICA Network, kConFab Investigators, Norwegian Breast Cancer Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Published: 2015

41. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Author: Lin, Wei-Yu, Camp, Nicola J, Ghoussaini, Maya, Beesley, Jonathan, Michailidou, Kyriaki, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Stone, Jennifer, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Th Rutgers, Emiel J, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Cheng, Timothy, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marmé, Frederik, Surowy, Harald M, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Mulot, Claire, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Menéndez, Primitiva, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Alvarez, Nuria, Herrero, Daniel, Anton-Culver, Hoda, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Müller-Myhsok, Bertram, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Horio, Akiyo, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Neven, Patrick, Wauters, Els, Wildiers, Hans, Lambrechts, Diether, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, and Flesch-Janys, Dieter
Subjects: GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Chromosomes, Human, Pair 2, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-Wide Association Study, Genotyping Techniques, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Prevention, Genetics, Human Genome, Breast Cancer, Cancer, Biotechnology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
Published: 2015

42. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

Author: Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise
Subjects: ABCTB Investigators, EMBRACE Group, GENICA Network, HEBON Group, kConFab Investigators, Humans, Carcinoma, Breast Neoplasms, Receptor, erbB-2, Receptors, Estrogen, Receptors, Progesterone, Neoplasm Staging, Likelihood Functions, Age Factors, Mutation, Genes, BRCA1, Genes, BRCA2, Adult, Aged, Middle Aged, Female, Neoplasm Grading, Triple Negative Breast Neoplasms, Receptor, ErbB-2, Receptor, erbB-2, Receptors, Estrogen, Progesterone, Genes, BRCA1, BRCA2, ErbB-2, Prevention, Breast Cancer, Cancer, Genetics, 4.2 Evaluation of markers and technologies, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionThe distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.MethodsSelection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ResultsER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).ConclusionsThese results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

43. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author: Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Prevention, Genetics, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adult, Age Factors, Aged, Breast Neoplasms, Carcinoma, Female, Genes, BRCA1, Genes, BRCA2, Humans, Likelihood Functions, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Triple Negative Breast Neoplasms, ABCTB Investigators, EMBRACE Group, GENICA Network, HEBON Group, kConFab Investigators, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

44. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Author: Purrington, Kristen, Slettedahl, Seth, Bolla, Manjeet, Michailidou, Kyriaki, Czene, Kamila, Nevanlinna, Heli, Bojesen, Stig, Andrulis, Irene, Cox, Angela, Hall, Per, Carpenter, Jane, Yannoukakos, Drakoulis, Haiman, Christopher, Fasching, Peter, Mannermaa, Arto, Winqvist, Robert, Brenner, Hermann, Lindblom, Annika, Chenevix-Trench, Georgia, Benitez, Javier, Swerdlow, Anthony, Kristensen, Vessela, Guénel, Pascal, Meindl, Alfons, Darabi, Hatef, Eriksson, Mikael, Fagerholm, Rainer, Aittomäki, Kristiina, Blomqvist, Carl, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Wang, Xianshu, Olswold, Curtis, Olson, Janet, Mulligan, Anna, Knight, Julia, Tchatchou, Sandrine, Reed, Malcolm, Cross, Simon, Liu, Jianjun, Li, Jingmei, Humphreys, Keith, Clarke, Christine, Scott, Rodney, Fostira, Florentia, Fountzilas, George, Konstantopoulou, Irene, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Ekici, Arif, Hartmann, Arndt, Beckmann, Matthias, Hartikainen, Jaana, Kosma, Veli-Matti, Kataja, Vesa, Jukkola-Vuorinen, Arja, Pylkäs, Katri, Kauppila, Saila, Dieffenbach, Aida, Stegmaier, Christa, Arndt, Volker, Margolin, Sara, Balleine, Rosemary, Arias Perez, Jose, Pilar Zamora, M, Menéndez, Primitiva, Ashworth, Alan, Jones, Michael, Orr, Nick, Arveux, Patrick, Kerbrat, Pierre, Truong, Thérèse, Bugert, Peter, Toland, Amanda, Ambrosone, Christine, Labrèche, France, Goldberg, Mark, Dumont, Martine, Ziogas, Argyrios, Lee, Eunjung, Dite, Gillian, Apicella, Carmel, Southey, Melissa, Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Ficarazzi, Filomena, Barile, Monica, Peterlongo, Paolo, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Tollenaar, Robert, Seynaeve, Caroline, Brüning, Thomas, Ko, Yon-Dschun, Van Deurzen, Carolien, Martens, John, and Kriege, Mieke
Subjects: Breast Neoplasms, Carrier Proteins, Case-Control Studies, Female, Genetic Variation, Haplotypes, Humans, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Risk Factors, Tumor Suppressor Proteins
Abstract: Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
Published: 2014

45. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author: Perry, John RB, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, de Geus, Eco EJ, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, and Kiel, Douglas P
Subjects: Paediatrics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Pediatric, Biotechnology, Human Genome, Clinical Research, Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Calcium-Binding Proteins, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins, Ubiquitin-Protein Ligases, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P
Published: 2014

46. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Author: Ghoussaini, Maya, Edwards, Stacey L, Michailidou, Kyriaki, Nord, Silje, Cowper-Sal Lari, Richard, Desai, Kinjal, Kar, Siddhartha, Hillman, Kristine M, Kaufmann, Susanne, Glubb, Dylan M, Beesley, Jonathan, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Guo, Qi, Schmidt, Marjanka K, Shah, Mitul, Luben, Robert, Brown, Judith, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Klevebring, Daniel, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Lambrechts, Diether, Thienpont, Bernard, Neven, Patrick, Wildiers, Hans, Broeks, Annegien, Van't Veer, Laura J, Th Rutgers, Emiel J, Couch, Fergus J, Olson, Janet E, Hallberg, Emily, Vachon, Celine, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, Dos-Santos-Silva, Isabel, Gibson, Lorna, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K, Noh, Dong-Young, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Qiuyin, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Lindblom, Annika, Margolin, Sara, and Teo, Soo Hwang
Subjects: Australian Ovarian Cancer Management Group, Cell Line, Tumor, Chromosomes, Human, Pair 2, Chromatin, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Insulin-Like Growth Factor Binding Protein 5, RNA, Messenger, Polymorphism, Single Nucleotide, Female, Hepatocyte Nuclear Factor 3-alpha, Promoter Regions, Genetic, MCF-7 Cells, Cell Line, Tumor, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger
Abstract: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Published: 2014

47. Alcohol Consumption and Survival after a Breast Cancer Diagnosis: A Literature-Based Meta-analysis and Collaborative Analysis of Data for 29,239 Cases

Author: Ali, Alaa MG, Schmidt, Marjanka K, Bolla, Manjeet K, Wang, Qin, Gago-Dominguez, M, Castelao, J Esteban, Carracedo, Angel, Garzón, Victor Muñoz, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Chang-Claude, Jenny, Vrieling, Alina, Rudolph, Anja, Seibold, Petra, Nevanlinna, Heli, Muranen, Taru A, Aaltonen, Kirsimari, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Horio, Akiyo, John, Esther M, Sherman, Mark, Lissowska, Jolanta, Figueroa, Jonine, Garcia-Closas, Montserrat, Anton-Culver, Hoda, Shah, Mitul, Hopper, John L, Trichopoulou, Antonia, Bueno-de-Mesquita, Bas, Krogh, Vittorio, Weiderpass, Elisabete, Andersson, Anne, Clavel-Chapelon, Françoise, Dossus, Laure, Fagherazzi, Guy, Peeters, Petra H, Olsen, Anja, Wishart, Gordon C, Easton, Douglas F, Borgquist, Signe, Overvad, Kim, Barricarte, Aurelio, González, Carlos A, Sánchez, María-José, Amiano, Pilar, Riboli, Elio, Key, Tim, and Pharoah, Paul D
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Substance Misuse, Breast Cancer, Cancer, Alcoholism, Alcohol Use and Health, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Oral and gastrointestinal, Good Health and Well Being, Adult, Aged, Alcohol Drinking, Breast Neoplasms, Cohort Studies, Female, Humans, Middle Aged, Prognosis, Risk Factors, Young Adult, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundEvidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts.MethodsA MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts.ResultsWe identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre- or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease.ConclusionThere was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease.ImpactConsidering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.
Published: 2014

48. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Author: Johnson, Nichola, Dudbridge, Frank, Orr, Nick, Gibson, Lorna, Jones, Michael E, Schoemaker, Minouk J, Folkerd, Elizabeth J, Haynes, Ben P, Hopper, John L, Southey, Melissa C, Dite, Gillian S, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Atsma, Femke, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Renner, Stefan P, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Therese, Cordina, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Bernstein, Leslie, Anton-Culver, Hoda, Ziogas, Argyrios, Clarke Dur, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Dieffenbach, Aida Karina, Meindl, Alfons, Heil, Joerg, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Dörk, Thilo, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, Beesley, Jonathan, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Van den Berg, David, Tseng, Chiu-Chen, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Pensotti, Valeria, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Haiman, Chris, Simard, Jacques, and Goldberg, Mark S
Subjects: GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Reproductive History, Risk Factors, Age Factors, Age of Onset, Premenopause, Menarche, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Cytochrome P-450 CYP3A, Genetic Association Studies, Human Genome, Aging, Clinical Research, Cancer, Genetics, Breast Cancer, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionWe have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.MethodsWe further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.ResultsWe confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).ConclusionsTo our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Published: 2014

49. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

Author: Purrington, Kristen, Slager, Susan, Eccles, Diana, Yannoukakos, Drakoulis, Fasching, Peter, Miron, Penelope, Carpenter, Jane, Chang-Claude, Jenny, Martin, Nicholas, Montgomery, Grant, Kristensen, Vessela, Goodfellow, Paul, Tapper, William, Rafiq, Sajjad, Gerty, Susan, Durcan, Lorraine, Konstantopoulou, Irene, Fostira, Florentia, Vratimos, Athanassios, Apostolou, Paraskevi, Konstanta, Irene, Kotoula, Vassiliki, Lakis, Sotiris, Dimopoulos, Meletios, Skarlos, Dimosthenis, Pectasides, Dimitrios, Fountzilas, George, Beckmann, Matthias, Hein, Alexander, Ruebner, Matthias, Ekici, Arif, Hartmann, Arndt, Schulz-Wendtland, Ruediger, Renner, Stefan, Janni, Wolfgang, Rack, Brigitte, Scholz, Christoph, Neugebauer, Julia, Andergassen, Ulrich, Lux, Michael, Haeberle, Lothar, Clarke, Christine, Pathmanathan, Nirmala, Rudolph, Anja, Flesch-Janys, Dieter, Nickels, Stefan, Olson, Janet, Ingle, James, Olswold, Curtis, Slettedahl, Seth, Eckel-Passow, Jeanette, Anderson, S, Visscher, Daniel, Cafourek, Victoria, Sicotte, Hugues, Prodduturi, Naresh, Weiderpass, Elisabete, Bernstein, Leslie, Ivanovich, Jennifer, Giles, Graham, Baglietto, Laura, Southey, Melissa, Kosma, Veli-Matti, Fischer, Hans-Peter, Reed, Malcom, Cross, Simon, Deming-Halverson, Sandra, Shrubsole, Martha, Cai, Qiuyin, Shu, Xiao-Ou, Daly, Mary, Weaver, Joellen, Ross, Eric, Klemp, Jennifer, Sharma, Priyanka, Torres, Diana, Rüdiger, Thomas, Wölfing, Heidrun, Ulmer, Hans-Ulrich, Försti, Asta, Khoury, Thaer, Kumar, Shicha, Pilarski, Robert, Shapiro, Charles, Greco, Dario, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Irwanto, Astrid, Liu, Jianjun, Pankratz, Vernon, Wang, Xianshu, Severi, Gianluca, Mannermaa, Arto, Easton, Douglas, Hall, Per, Brauch, Hiltrud, Cox, Angela, Zheng, Wei, and Godwin, Andrew
Subjects: Adult, Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 19, Estrogen Receptor alpha, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Triple Negative Breast Neoplasms, Young Adult
Abstract: Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Published: 2014

50. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.

Author: Milne, Roger, Herranz, Jesús, Michailidou, Kyriaki, Dennis, Joe, Tyrer, Jonathan, Zamora, M, Arias-Perez, José, González-Neira, Anna, Pita, Guillermo, Alonso, M, Wang, Qin, Bolla, Manjeet, Czene, Kamila, Eriksson, Mikael, Humphreys, Keith, Darabi, Hatef, Li, Jingmei, Orr, Nicholas, Schoemaker, Minouk, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Andrulis, Irene, Knight, Julia, Glendon, Gord, Mulligan, Anna, Bojesen, Stig, Nordestgaard, Børge, Flyger, Henrik, Nevanlinna, Heli, Muranen, Taru, Aittomäki, Kristiina, Blomqvist, Carl, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Wang, Xianshu, Olson, Janet, Vachon, Celine, Purrington, Kristen, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Dunning, Alison, Shah, Mitul, Guénel, Pascal, Truong, Thérèse, Sanchez, Marie, Mulot, Claire, Brenner, Hermann, Dieffenbach, Aida, Arndt, Volker, Stegmaier, Christa, Lindblom, Annika, Margolin, Sara, Hooning, Maartje, Hollestelle, Antoinette, Collée, J, Jager, Agnes, Cox, Angela, Brock, Ian, Reed, Malcolm, Devilee, Peter, Tollenaar, Robert, Seynaeve, Caroline, Haiman, Christopher, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Dumont, Martine, Soucy, Penny, Dörk, Thilo, Bogdanova, Natalia, Hamann, Ute, Försti, Asta, Rüdiger, Thomas, Ulmer, Hans-Ulrich, Fasching, Peter, Häberle, Lothar, Ekici, Arif, Beckmann, Matthias, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Radice, Paolo, Peterlongo, Paolo, Peissel, Bernard, Mariani, Paolo, Giles, Graham, Severi, Gianluca, Baglietto, Laura, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, and Miller, Nicola
Subjects: Breast Neoplasms, Case-Control Studies, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide
Abstract: Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
Published: 2014

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