Author: "Cross, Simon S." - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Cross, Simon S."' showing total 1,279 results

Start Over Author "Cross, Simon S."

1,279 results on '"Cross, Simon S."'

1. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author: Levi, Hagai, Carmi, Shai, Rosset, Saharon, Yerushalmi, Rinat, Zick, Aviad, Yablonski-Peretz, Tamar, Consortium, The BCAC, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura Beane, Beckmann, Matthias, Behrens, Sabine, Bermisheva, Marina, Bodelon, Clara, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Byers, Helen, Camp, Nicola, Castelao, Jose, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chung, Wendy, Clarke, Christine, Collaborators, NBCS, Collee, Margriet J, Colonna, Sarah, Consortium, CTS, Couch, Fergus, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary, Devilee, Peter, Dork, Thilo, Dossus, Laure, Eccles, Diana M, Eliassen, A Heather, Eriksson, Mikael, Evans, Gareth, Fasching, Peter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Garcia-Saenz, Jose Angel, Genkinger, Jeanine, Giles, Graham G, Goldberg, Mark, Guénel, Pascal, Hall, Per, Hamann, Ute, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John, Investigators, ABCTB, Jakovchevska, Simona, Jakubowska, Anna, Jernström, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Vijai, Joseph, Kaaks, Rudolf, Khusnutdinova, Elza, Kitahara, Cari, Koutros, Stella, Kristensen, Vessela, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Loibl, Sibylle, Lori, Adriana, Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Mavroudis, Dimitrios, Menon, Usha, Mulligan, AnnaMarie, Murphy, Rachel, Nevelsteen, Ines, Newman, William G, and Obi, Nadia
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Prevention, Cancer, Humans, Female, Breast Neoplasms, Genome-Wide Association Study, Jews, Israel, Genetic Predisposition to Disease, Risk Factors, Multifactorial Inheritance, Transcription Factors, Genomics, Polymorphism, Genetic, BCAC Consortium, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Polymorphism, Genetic, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Published: 2023

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

Author: Morra, Anna, Schreurs, Maartje AC, Andrulis, Irene L, Anton‐Culver, Hoda, Augustinsson, Annelie, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Broeks, Annegien, Buys, Saundra S, Camp, Nicola J, Castelao, Jose E, Cessna, Melissa H, Chang‐Claude, Jenny, Chung, Wendy K, Sahlberg, Kristine K, Børresen‐Dale, Anne‐Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Alnæs, Grethe I Grenaker, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fehm, Tanja N, Figueroa, Jonine D, Flyger, Henrik, Gabrielson, Marike, Gago‐Dominguez, Manuela, García‐Closas, Montserrat, García‐Sáenz, José A, Genkinger, Jeanine, Grassmann, Felix, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, J Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, Chenevix‐Trench, Georgia, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Courtney, Eliza, Cummings, Margaret, and Dawson, Sarah‐Jane
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Clinical Research, Prevention, Women's Health, Female, Humans, Breast Neoplasms, Checkpoint Kinase 2, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Proportional Hazards Models, CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Biochemistry and Cell Biology, Oncology and carcinogenesis
Abstract: BackgroundBreast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.AimTo assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.MethodsAnalyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.ResultsThere was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].ConclusionSystemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
Published: 2023

3. 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

4. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author: Middha, Pooja, Wang, Xiaoliang, Behrens, Sabine, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baert, Thaïs, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Benitez, Javier, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dossus, Laure, Dugué, Pierre-Antoine, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Giles, Graham G, González-Neira, Anna, Grassmann, Felix, Grundy, Anne, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Holleczek, Bernd, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ingvar, Christian, Isaksson, Karolin, Jernström, Helena, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Larsson, Susanna, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Shuai, Linet, Martha, Lissowska, Jolanta, Martinez, Maria Elena, Maurer, Tabea, Mulligan, Anna Marie, Mulot, Claire, Murphy, Rachel A, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, O’Brien, Katie M, Olson, Janet E, Patel, Alpa V, Prentice, Ross, Rees-Punia, Erika, Rennert, Gad, Rhenius, Valerie, Ruddy, Kathryn J, and Sandler, Dale P
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer Genomics, Human Genome, Estrogen, Cancer, Women's Health, Genetics, Prevention, Aging, Breast Cancer, 2.1 Biological and endogenous factors, Adult, Female, Humans, Gene-Environment Interaction, Genetic Predisposition to Disease, Breast Neoplasms, Bayes Theorem, Genome-Wide Association Study, Risk Factors, Polymorphism, Single Nucleotide, Case-Control Studies, Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, CTS Consortium, ABCTB Investigators, kConFab Investigators, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundGenome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability
Published: 2023

5. Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer

Author: Wichert, Katharina, Hoppe, Reiner, Ickstadt, Katja, Behrens, Thomas, Winter, Stefan, Herold, Robert, Terschüren, Claudia, Lo, Wing-Yee, Guénel, Pascal, Truong, Thérèse, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Andrulis, Irene L., Brenner, Hermann, Chang-Claude, Jenny, Cox, Angela, Cross, Simon S., Czene, Kamila, Eriksson, Mikael, Figueroa, Jonine D., García-Closas, Montserrat, Goldberg, Mark S., Hamann, Ute, He, Wei, Holleczek, Bernd, Hopper, John L., Jakubowska, Anna, Ko, Yon-Dschun, Lubiński, Jan, Mulligan, Anna Marie, Obi, Nadia, Rhenius, Valerie, Shah, Mitul, Shu, Xiao-Ou, Simard, Jacques, Southey, Melissa C., Zheng, Wei, Dunning, Alison M., Pharoah, Paul D. P., Hall, Per, Easton, Douglas F., Brüning, Thomas, Brauch, Hiltrud, Harth, Volker, and Rabstein, Sylvia
Published: 2023
Full Text: View/download PDF

6. 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

7. 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

8. Accuracy of the No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: A Systematic Review and Meta-Analysis

Author: Shiha, Mohamed G., Nandi, Nicoletta, Raju, Suneil A., Wild, Graeme, Cross, Simon S., Singh, Prashant, Elli, Luca, Makharia, Govind K., Sanders, David S., and Penny, Hugo A.
Published: 2024
Full Text: View/download PDF

9. 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

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

Author: Dennis, Joe, Tyrer, Jonathan P, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Qin, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, and Soucy, Penny
Subjects: Human Genome, Breast Cancer, Genetics, Clinical Research, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Case-Control Studies, DNA Copy Number Variations, Female, Genome, Human, Genome-Wide Association Study, Germ Cells, Humans, Risk Factors, NBCS Collaborators, CTS Consortium, ABCTB Investigators, kConFab/AOCS Investigators
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value
Published: 2022

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

Author: Morra, Anna, Escala-Garcia, Maria, Beesley, Jonathan, Keeman, Renske, Canisius, Sander, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Caan, Bette, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Ting-Yuan David, Clarke, Christine L, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Dörk, Thilo, Dossus, Laure, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, Gago-Dominguez, Manuela, García-Sáenz, José A, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Hartikainen, Jaana M, Hartmann, Arndt, He, Wei, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Keupers, Machteld, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Linet, Martha, Luben, Robert N, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martens, John WM, Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L, Mulligan, Anna Marie, Muranen, Taru A, Nevanlinna, Heli, Newman, William G, and Nielsen, Sune F
Subjects: Clinical Research, Cancer, Breast Cancer, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis, Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundGiven the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.MethodsWe performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP
Published: 2021

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

Author: Park, Hanla A, Neumeyer, Sonja, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baten, Adinda, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny, Harkness, Elaine F, Hart, Steven N, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hopper, John L, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lo, Wing-Yee, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Meindl, Alfons, Menon, Usha, Milne, Roger L, Muranen, Taru A, and Nevanlinna, Heli
Subjects: Genetics, Cancer, Substance Misuse, Clinical Research, Human Genome, Prevention, Drug Abuse (NIDA only), Breast Cancer, Tobacco, Tobacco Smoke and Health, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

13. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul RHJ, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, and Heiss, Gerardo
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Estrogen, Prevention, Women's Health, Contraception/Reproduction, Aging, Infertility, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Good Health and Well Being, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Europe, Asia, Eastern, Female, Fertility, Fragile X Mental Retardation Protein, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging, Humans, Longevity, Menopause, Menopause, Premature, Mice, Mice, Inbred C57BL, Middle Aged, Ovary, Primary Ovarian Insufficiency, Uterus, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, LifeLines Cohort Study, InterAct consortium, 23andMe Research Team, General Science & Technology
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

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

Author: Baxter, Joseph S, Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Brucker, Sara Y, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, Collaborators, NBCS, Colonna, Sarah, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, García-Closas, Montserrat, García-Sáenz, José A, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hou, Ming-Feng, Investigators, kConFab, Investigators, ABCTB, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, and Lacey, James V
Subjects: Human Genome, Genetics, Cancer, Estrogen, Prevention, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, CRISPR-Cas Systems, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 2, Female, Genetic Association Studies, Genetic Variation, Humans, Insulin-Like Growth Factor Binding Protein 5, Molecular Sequence Annotation, Promoter Regions, Genetic, Risk Factors, Sequence Deletion, NBCS Collaborators, kConFab Investigators, ABCTB Investigators, breast cancer risk, functional annotation, risk locus, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
Published: 2021

15. 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

16. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

Author: Kapoor, Pooja Middha, Mavaddat, Nasim, Choudhury, Parichoy Pal, Wilcox, Amber N, Lindström, Sara, Behrens, Sabine, Michailidou, Kyriaki, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Jung, Audrey, Abu-Ful, Zomoroda, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chatterjee, Nilanjan, Chenevix-Trench, Georgia, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Earp, H Shelton, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hatse, Sigrid, Heyworth, Jane, Holleczek, Bernd, Hoover, Robert N, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab/AOCS Investigators, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, MacInnis, Robert J, Martinez, Maria Elena, Maurer, Tabea, McLean, Catriona, Neuhausen, Susan L, Newman, William G, Norman, Aaron, O'Brien, Katie M, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, and Orr, Nick
Subjects: ABCTB Investigators, kConFab/AOCS Investigators, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Published: 2021

17. 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

18. Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Author: Park, JooYong, Choi, Ji-Yeob, Choi, Jaesung, Chung, Seokang, Song, Nan, Park, Sue K, Han, Wonshik, Noh, Dong-Young, Ahn, Sei-Hyun, Lee, Jong Won, Kim, Mi Kyung, Jee, Sun Ha, Wen, Wanqing, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Shah, Mitul, Conroy, Don M, Harrington, Patricia A, Mayes, Rebecca, Czene, Kamila, Hall, Per, Teras, Lauren R, Patel, Alpa V, Couch, Fergus J, Olson, Janet E, Sawyer, Elinor J, Roylance, Rebecca, Bojesen, Stig E, Flyger, Henrik, Lambrechts, Diether, Baten, Adinda, Matsuo, Keitaro, Ito, Hidemi, Guénel, Pascal, Truong, Thérèse, Keeman, Renske, Schmidt, Marjanka K, Wu, Anna H, Tseng, Chiu-Chen, Cox, Angela, Cross, Simon S, kConFab Investigators, Andrulis, Irene L, Hopper, John L, Southey, Melissa C, Wu, Pei-Ei, Shen, Chen-Yang, Fasching, Peter A, Ekici, Arif B, Muir, Kenneth, Lophatananon, Artitaya, Brenner, Hermann, Arndt, Volker, Jones, Michael E, Swerdlow, Anthony J, Hoppe, Reiner, Ko, Yon-Dschun, Hartman, Mikael, Li, Jingmei, Mannermaa, Arto, Hartikainen, Jaana M, Benitez, Javier, González-Neira, Anna, Haiman, Christopher A, Dörk, Thilo, Bogdanova, Natalia V, Teo, Soo Hwang, Mohd Taib, Nur Aishah, Fletcher, Olivia, Johnson, Nichola, Grip, Mervi, Winqvist, Robert, Blomqvist, Carl, Nevanlinna, Heli, Lindblom, Annika, Wendt, Camilla, Kristensen, Vessela N, Nbcs Collaborators, Tollenaar, Rob AEM, Heemskerk-Gerritsen, Bernadette AM, Radice, Paolo, Bonanni, Bernardo, Hamann, Ute, Manoochehri, Mehdi, Lacey, James V, Martinez, Maria Elena, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Yoo, Keun-Young, and Kang, Daehee
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Estrogen, Prevention, Aging, Genetics, Women's Health, Clinical Research, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, breast cancer, estrogen, gene-environment interaction, Oncology and carcinogenesis
Abstract: In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
Published: 2021

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

Author: Kramer, Iris, Hooning, Maartje J, Mavaddat, Nasim, Hauptmann, Michael, Keeman, Renske, Steyerberg, Ewout W, Giardiello, Daniele, Antoniou, Antonis C, Pharoah, Paul DP, Canisius, Sander, Abu-Ful, Zumuruda, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Bremer, Michael, Brucker, Sara Y, Burwinkel, Barbara, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hopper, John L, Hou, Ming-Feng, Howell, Anthony, Ito, Hidemi, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kets, C Marleen, Khusnutdinova, Elza, Ko, Yon-Dschun, Kristensen, Vessela N, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger, Mulligan, Anna Marie, Muranen, Taru A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, and Peto, Julian
Subjects: Breast Cancer, Prevention, Cancer, Adult, Aged, Asian People, Breast Neoplasms, Cohort Studies, Estrogen Receptor alpha, Female, Gene Expression, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Multifactorial Inheritance, Neoadjuvant Therapy, Neoplasms, Second Primary, Prognosis, Proportional Hazards Models, Receptor, ErbB-2, Receptors, Progesterone, Risk Assessment, White People, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Receptor, erbB-2, contralateral breast cancer, epidemiology, genetic, polygenic risk score, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
Published: 2020

20. 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

21. 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

22. Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium

Author: Kapoor, Pooja Middha, Lindström, Sara, Behrens, Sabine, Wang, Xiaoliang, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dunning, Alison M, Pharoah, Paul DP, Schmidt, Marjanka K, Kraft, Peter, García-Closas, Montserrat, Easton, Douglas F, Milne, Roger L, Chang-Claude, Jenny, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bernstein, Leslie, Berrandou, Takiy, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Butterbach, Katja, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Clarke, Christine L, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Dite, Gillian S, Earp, H Shelton, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Grundy, Anne, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Harstad, Tricia, He, Wei, Heyworth, Jane, Hoover, Robert N, Hopper, John L, Humphreys, Keith, Hunter, David J, Marrón, Pablo Isidro, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Krüger, Ute, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, and Makalic, Enes
Subjects: Genetics, Estrogen, Clinical Research, Cancer, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Europe, Factor XIII, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, Breast Cancer Association Consortium, Europeans, Gene-environment interaction, breast cancer, epidemiology, risk factors, single nucleotide polymorphism, Statistics, Public Health and Health Services, Epidemiology
Abstract: BackgroundPrevious gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.MethodsAnalyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.ResultsNoteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.ConclusionsOverall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.
Published: 2020

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. Coeliac Disease and Microscopic Colitis: The Largest Study Assessing Prognosis and Risk of Hospital Admission.

Author: Raju, Suneil A., Rawcliffe, Megan E., Bowker-Howell, Freya J., Shiha, Mohamed G., Kaur, Kamaldeep E., Griffin, Jonathan, Cross, Simon S., and Sanders, David S.
Abstract: Microscopic colitis (MC) and coeliac disease (CD) are common associated gastrointestinal conditions. We present the largest study assessing hospitalisation in patients with MC and the effect of a concomitant diagnosis of CD. Data were retrospectively collected between January 2007 and December 2021 from all patients diagnosed with MC and compared to a database of patients with only CD. In total, 892 patients with MC (65% female, median age 65 years (IQR: 54–74 years) were identified, with 6.4% admitted to hospital due to a flare of MC. Patients admitted were older (76 vs. 65 years, p < 0.001) and presented with diarrhoea (87.7%), abdominal pain (26.3%), and acute kidney injury (17.5%). Treatment was given in 75.9% of patients, including intravenous fluids (39.5%), steroids (20.9%), and loperamide (16.3%). Concomitant CD was diagnosed in 3.3% of patients and diagnosed before MC (57 versus 64 years, p < 0.001). Patients with both conditions were diagnosed with CD later than patients with only CD (57 years versus 44 years, p < 0.001). In conclusion, older patients are at a higher risk of hospitalisation due to MC, and this is seen in patients with a concomitant diagnosis of CD too. Patients with MC are diagnosed with CD later than those without. [ABSTRACT FROM AUTHOR]
Published: 2024
Full Text: View/download PDF

30. New entity of adult ultra-short coeliac disease: the first international cohort and case–control study.

Author: Raju, Suneil A., Greenaway, Emily A., Schiepatti, Annalisa, Arpa, Giovanni, Vecchione, Nicoletta, Jian, Chao L. A., Grobler, Charlotte, Maregatti, Margherita, Green, Olivia, Bowker-Howell, Freya J., Shiha, Mohamed G., Penny, Hugo A., Cross, Simon S., Ciacci, Carolina, Rostami, Kamran, Ahmadipour, Shokoufeh, Moradi, Afshin, Rostami-Nejad, Mohammad, Biagi, Federico, and Volta, Umberto
Subjects: CELIAC disease, ADULTS, MEDICAL care
Published: 2024
Full Text: View/download PDF

31. 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, Cancer, Breast Cancer, Human Genome, Prevention, Women's Health, Cancer Genomics, Biotechnology, 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

32. The BRCA2 c.68‐7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author: Colombo, Mara, Lòpez‐Perolio, Irene, Meeks, Huong D, Caleca, Laura, Parsons, Michael T, Li, Hongyan, Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B Gómez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y, Varesco, Liliana, Wappenschmidt, Barbara, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Aittomäki, Kristiina, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly‐Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Chang‐Claude, Jenny, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, García‐Closas, Montserrat, Giles, Graham G, González‐Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L, Jakubowska, Anna, Jung, Audrey, Kosma, Veli‐Matti, Lambrechts, Diether, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Peterlongo, Paolo, Peto, Julian, Pylkäs, Katri, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, See, Mee Hoong, Southey, Melissa C, Swerdlow, Anthony, Teo, Soo H, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Asperen, Christi J, Ouweland, Ans MW den, der Kolk, Lizet E, Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, Investigators, kConFab AOCS, Dunning, Alison M, and Easton, Douglas F
Subjects: Cancer, Genetics, Clinical Research, Prevention, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA2 Protein, Base Sequence, Calibration, Cell Line, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Mitomycin, Models, Genetic, RNA Splicing, RNA, Messenger, kConFab/AOCS Investigators, BRCA2, digital PCR, multifactorial likelihood analysis, quantitative real-time PCR, spliceogenic variants, Clinical Sciences, Genetics & Heredity
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

33. Publisher Correction: 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, Rutgers, Emiel J Th, 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, Pilar Zamora, M, 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
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

34. Correction: Publisher Correction: 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, Rutgers, Emiel J Th, 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, Pilar Zamora, M, 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: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

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

Author: Jiao, Xiang, Aravidis, Christos, Marikkannu, Rajeshwari, Rantala, Johanna, Picelli, Simone, Adamovic, Tatjana, Liu, Tao, Maguire, Paula, Kremeyer, Barbara, Luo, Liping, von Holst, Susanna, Kontham, Vinaykumar, Thutkawkorapin, Jessada, Margolin, Sara, Du, Quan, Lundin, Johanna, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Beckmann, Matthias W, Blomqvist, Carl, Blot, William, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Chang-Claude, Jenny, Couch, Fergus J, Cox, Angela, Cross, Simon S, Deming-Halverson, Sandra L, Devilee, Peter, dos-Santos-Silva, Isabel, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Guo, Qi, Gündert, Melanie, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hooning, Maartje J, Hopper, John L, Huang, Guanmengqian, Jakubowska, Anna, Jones, Michael E, Kerin, Michael J, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lubinski, Jan, Mannermaa, Arto, Martens, John WM, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Peto, Julian, Pylkäs, Katri, Radice, Paolo, Rhenius, Valerie, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Southey, Melissa C, Swerdlow, Anthony J, Truong, Thérèse, Wendt, Camilla, Winqvist, Robert, Zheng, Wei, Benitez, Javier, Dunning, Alison M, and Pharoah, Paul DP
Subjects: Cancer, Prevention, Breast Cancer, Genetics, Human Genome, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, familial breast cancer, linkage analysis, risk haplotype, sequencing, NBCS Collaborators, kConFab/AOCS Investigators, Oncology and Carcinogenesis
Abstract: Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
Published: 2017

36. 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

37. Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction

Author: Yiangou, Kristia, primary, Mavaddat, Nasim, additional, Dennis, Joe, additional, Zanti, Maria, additional, Wang, Qin, additional, Bolla, Manjeet K., additional, Abubakar, Mustapha, additional, Ahearn, Thomas U., additional, Andrulis, Irene L., additional, Anton-Culver, Hoda, additional, Antonenkova, Natalia N., additional, Arndt, Volker, additional, Aronson, Kristan J., additional, Augustinsson, Annelie, additional, Baten, Adinda, additional, Behrens, Sabine, additional, Bermisheva, Marina, additional, Berrington de Gonzalez, Amy, additional, Bialkowska, Katarzyna, additional, Boddicker, Nicholas, additional, Bodelon, Clara, additional, Bogdanova, Natalia V., additional, Bojesen, Stig E., additional, Brantley, Kristen D., additional, Brauch, Hiltrud, additional, Brenner, Hermann, additional, Camp, Nicola J., additional, Canzian, Federico, additional, Castelao, Jose E., additional, Cessna, Melissa H., additional, Chang-Claude, Jenny, additional, Chenevix-Trench, Georgia, additional, Chung, Wendy K., additional, Collaborators, NBCS, additional, Colonna, Sarah V., additional, Couch, Fergus J., additional, Cox, Angela, additional, Cross, Simon S., additional, Czene, Kamila, additional, Daly, Mary B., additional, Devilee, Peter, additional, Dork, Thilo, additional, Dunning, Alison M., additional, Eccles, Diana M., additional, Eliassen, A. Heather, additional, Engel, Christoph, additional, Eriksson, Mikael, additional, Evans, D. Gareth, additional, Fasching, Peter A., additional, Fletcher, Olivia, additional, Flyger, Henrik, additional, Fritschi, Lin, additional, Gago-Dominguez, Manuela, additional, Gentry-Maharaj, Aleksandra, additional, Gonzalez-Neira, Anna, additional, Guenel, Pascal, additional, Hahnen, Eric, additional, Haiman, Christopher A., additional, Hamann, Ute, additional, Hartikainen, Jaana M., additional, Ho, Vikki, additional, Hodge, James, additional, Hollestelle, Antoinette, additional, Honisch, Ellen, additional, Hooning, Maartje J., additional, Hoppe, Reiner, additional, Hopper, John L., additional, Howell, Sacha, additional, Howell, Anthony, additional, Investigators, ABCTB, additional, Investigators, kConFab, additional, Jakovchevska, Simona, additional, Jakubowska, Anna, additional, Jernstrom, Helena, additional, Johnson, Nichola, additional, Kaaks, Rudolf, additional, Khusnutdinova, Elza K., additional, Kitahara, Cari M., additional, Koutros, Stella, additional, Kristensen, Vessela N., additional, Lacey, James V., additional, Lambrechts, Diether, additional, Lejbkowicz, Flavio, additional, Lindblom, Annika, additional, Lush, Michael, additional, Mannermaa, Arto, additional, Mavroudis, Dimitrios, additional, Menon, Usha, additional, Murphy, Rachel A., additional, Nevanlinna, Heli, additional, Obi, Nadia, additional, Offit, Kenneth, additional, Park-Simon, Tjoung-Won, additional, Patel, Alpa V., additional, Peng, Cheng, additional, Peterlongo, Paolo, additional, Pita, Guillermo, additional, Plaseska-Karanfilska, Dijana, additional, Pylkas, Katri, additional, Radice, Paolo, additional, Rashid, Muhammad U., additional, Rennert, Gad, additional, Roberts, Eleanor, additional, Rodriguez, Juan, additional, Romero, Atocha, additional, Rosenberg, Efraim H., additional, Saloustros, Emmanouil, additional, Sandler, Dale P., additional, Sawyer, Elinor J., additional, Schmutzler, Rita K., additional, Scott, Christopher G., additional, Shu, Xiao-Ou, additional, Southey, Melissa C., additional, Stone, Jennifer, additional, Taylor, Jack A., additional, Teras, Lauren R., additional, van de Beek, Irma, additional, Willett, Walter, additional, Winqvist, Robert, additional, Zheng, Wei, additional, Vachon, Celine M., additional, Schmidt, Marjanka K., additional, Hall, Per, additional, MacInnis, Robert J., additional, Milne, Roger L., additional, Pharoah, Paul D.P., additional, Simard, Jacques, additional, Antoniou, Antonis C., additional, Easton, Douglas F., additional, and Michailidou, Kyriaki, additional
Published: 2024
Full Text: View/download PDF

38. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Author: Shimelis, Hermela, Mesman, Romy LS, Von Nicolai, Catharina, Ehlen, Asa, Guidugli, Lucia, Martin, Charlotte, Calléja, Fabienne MGR, Meeks, Huong, Hallberg, Emily, Hinton, Jamie, Lilyquist, Jenna, Hu, Chunling, Aalfs, Cora M, Aittomäki, Kristiina, Andrulis, Irene, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Benitez, Javier, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Broeks, Annegien, Brouwers, Barbara, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cheng, Ching-Yu, Choi, Ji-Yeob, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Dennis, Joe, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, García-Closas, Montserrat, Giles, Graham G, Glendon, Gord, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hogervorst, Frans B, Hollestelle, Antoinette, Hopper, John L, Ito, Hidemi, Jakubowska, Anna, Kang, Daehee, Kosma, Veli-Matti, Kristensen, Vessela, Lai, Kah-Nyin, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Machackova, Eva, Mannermaa, Arto, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, Miao, Hui, Michailidou, Kyriaki, Milne, Roger L, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Olswold, Curtis, Oosterwijk, Jan JC, Osorio, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Pylkäs, Katri, Radice, Paolo, Rashid, Muhammad Usman, Rhenius, Valerie, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schoemaker, Minouk J, Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, and Shrubsole, Martha
Subjects: Breast Cancer, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Aged, Amino Acid Substitution, Animals, BRCA2 Protein, Breast Neoplasms, Case-Control Studies, Female, Genotype, Germ-Line Mutation, Humans, Mice, Mutation, Missense, Risk, for kConFab/AOCS Investigators, for NBCS Collaborators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.
Published: 2017

39. 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

40. 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

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

Author: Ghoussaini, Maya, French, Juliet D, Michailidou, Kyriaki, Nord, Silje, Beesley, Jonathan, Canisus, Sander, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Marjaneh, Moradi, Lee, Jason S, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Milne, Roger L, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Alonso, M Rosario, Pita, Guillermo, Neuhausen, Susan L, Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Tessier, Daniel C, Vincent, Daniel, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Investigators, kConFab AOCS, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Barile, Monica, Couch, Fergus J, Hallberg, Emily, Giles, Graham G, Haiman, Christopher A, Le Marchand, Loic, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Borresen-Dale, Anne-Lise, Collaborators, NBCS, Zheng, Wei, Cai, Qiuyin, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Devilee, Peter, Tollenaar, Rob AEM, García-Closas, Montserrat, Figueroa, Jonine, Hall, Per, Czene, Kamila, Brand, Judith S, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J, Koppert, Linetta B, Li, Jingmei, Shu, Xiao-Ou, Zheng, Ying, Cox, Angela, Cross, Simon S, Shah, Mitul, and Rhenius, Valerie
Subjects: Prevention, Genetics, Cancer, Breast Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosomes, Human, Pair 5, Enhancer Elements, Genetic, Fibroblast Growth Factor 10, Genetic Predisposition to Disease, Haplotypes, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, kConFab/AOCS Investigators, NBCS Collaborators, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Published: 2016

42. Fine‐scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author: Shi, Jiajun, Zhang, Yanfeng, Zheng, Wei, Michailidou, Kyriaki, Ghoussaini, Maya, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Milne, Roger L, Shu, Xiao‐Ou, Beesley, Jonathan, Kar, Siddhartha, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Zhao, Zhiguo, Guo, Xingyi, Benitez, Javier, Beeghly‐Fadiel, Alicia, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang‐Claude, Jenny, Choi, Ji‐Yeob, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dork, Thilo, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García‐Closas, Montserrat, Giles, Graham G, Grip, Mervi, Guenel, Pascal, Haiman, Christopher A, Hamann, Ute, Hartman, Mikael, Miao, Hui, Hollestelle, Antoinette, Hopper, John L, Hsiung, Chia‐Ni, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Torres, Diana, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia A, Kosma, Veli‐Matti, Lambrechts, Diether, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Nord, Silje, Børresen‐Dale, Anne‐Lise, Olson, Janet E, Orr, Nick, van den Ouweland, Ans MW, Peterlongo, Paolo, Putti, Thomas Choudary, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shen, Chen‐Yang, Hou, Ming‐Feng, Shrubsole, Matha J, and Southey, Melissa C
Subjects: Genetics, Cancer, Breast Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 8, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, White People, breast cancer, genetic susceptibility, 8q24, fine-mapping, single nucleotide polymorphism, Mervi Grip, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
Published: 2016

43. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).

Author: Darabi, Hatef, Beesley, Jonathan, Droit, Arnaud, Kar, Siddhartha, Nord, Silje, Moradi Marjaneh, Mahdi, Soucy, Penny, Michailidou, Kyriaki, Ghoussaini, Maya, Fues Wahl, Hanna, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Benitez, Javier, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Choi, Ji-Yeob, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Easton, Douglas F, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Galle, Eva, García-Closas, Montserrat, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, Hartman, Mikael, Hollestelle, Antoinette, Hopper, John L, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Kang, Daehee, Khan, Sofia, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Lambrechts, Diether, Le Marchand, Loic, Lee, Soo Chin, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Mayes, Rebecca, McKay, James, Meindl, Alfons, Milne, Roger L, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Olswold, Curtis, Orr, Nick, Peterlongo, Paolo, Pita, Guillermo, Pylkäs, Katri, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Stram, Daniel O, Surowy, Harald, Swerdlow, Anthony, Teo, Soo H, Tessier, Daniel C, Tomlinson, Ian, Torres, Diana, and Truong, Thérèse
Abstract: Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Published: 2016

44. 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

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

Author: Guo, Yan, Warren Andersen, Shaneda, Shu, Xiao-Ou, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Garcia-Closas, Montserrat, Milne, Roger L, Schmidt, Marjanka K, Chang-Claude, Jenny, Dunning, Allison, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bogdanova, Natalia V, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, 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, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, Jenkins, Mark, John, Esther M, Johnson, Nichola, Jones, Michael E, Kabisch, Maria, Kibriya, Muhammad, Knight, Julia A, Koppert, Linetta B, Kosma, Veli-Matti, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Luben, Robert, Lubinski, Jan, Malone, Kathi E, Mannermaa, Arto, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perez, Jose IA, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Shrubsole, Martha J, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob B, and Verhoef, Senno
Subjects: Humans, Breast Neoplasms, Genetic Predisposition to Disease, Body Mass Index, Models, Statistical, Risk Factors, Menopause, Polymorphism, Single Nucleotide, Middle Aged, European Continental Ancestry Group, Female, Mendelian Randomization Analysis, Models, Statistical, Polymorphism, Single Nucleotide, Genetics, Prevention, Breast Cancer, Nutrition, Clinical Research, Cancer, Aging, Human Genome, 2.1 Biological and endogenous factors, General & Internal Medicine, Medical and Health Sciences
Abstract: BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p
Published: 2016

46. Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Author: Schmidt, Marjanka K, Hogervorst, Frans, van Hien, Richard, Cornelissen, Sten, Broeks, Annegien, Adank, Muriel A, Meijers, Hanne, Waisfisz, Quinten, Hollestelle, Antoinette, Schutte, Mieke, van den Ouweland, Ans, Hooning, Maartje, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Antoniou, Antonis C, Arndt, Volker, Bermisheva, Marina, Bogdanova, Natalia V, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dunning, Alison M, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Galle, Eva, García-Closas, Montserrat, Giles, Graham G, Haeberle, Lothar, Hall, Per, Hillemanns, Peter, Hopper, John L, Jakubowska, Anna, John, Esther M, Jones, Michael, Khusnutdinova, Elza, Knight, Julia A, Kosma, Veli-Matti, Kristensen, Vessela, Lee, Andrew, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Meindl, Alfons, Milne, Roger L, Muranen, Taru A, Newcomb, Polly A, Offit, Kenneth, Park-Simon, Tjoung-Won, Peto, Julian, Pharoah, Paul DP, Robson, Mark, Rudolph, Anja, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Soens, Julie, Southey, Melissa C, Spurdle, Amanda B, Surowy, Harald, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Trentham-Dietz, Amy, Vachon, Celine, Wang, Qin, Whittemore, Alice S, Ziogas, Argyrios, van der Kolk, Lizet, Nevanlinna, Heli, Dörk, Thilo, Bojesen, Stig, and Easton, Douglas F
Subjects: Clinical Research, Genetics, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Middle Aged, Odds Ratio, Receptors, Estrogen, Receptors, Progesterone, Risk Assessment, Sequence Deletion, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeCHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and methodsCHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Published: 2016

47. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Zeng, Chenjie, Guo, Xingyi, Long, Jirong, Kuchenbaecker, Karoline B, Droit, Arnaud, Michailidou, Kyriaki, Ghoussaini, Maya, Kar, Siddhartha, Freeman, Adam, Hopper, John L, Milne, Roger L, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Agata, Simona, Ahmed, Shahana, AittomÃ¤ki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Arun, Banu K, Arver, Brita, Bacot, Francois, Barrowdale, Daniel, Baynes, Caroline, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William J, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Broeks, Annegien, BrÃ¼ning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Carpenter, Jane, Chang-Claude, Jenny, Choi, Ji-Yeob, Claes, Kathleen B. M, Clarke, Christine, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, De Leeneer, Kim, Devilee, Peter, Diez, Orland, Domchek, Susan M, Doody, Michele, Dorfling, Cecilia M, DÃ¶rk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Dworniczak, Bernd, Egan, Kathleen, Eilber, Ursula, Einbeigi, Zakaria, Ejlertsen, Bent, Ellis, Steve, Frost, Debra, Lalloo, Fiona, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Friedlander, Michael, Friedman, Eitan, Gambino, Gaetana, Gao, Yu-Tang, Garber, Judy, GarcÃa-Closas, Montserrat, Gehrig, Andrea, Damiola, Francesca, Lesueur, Fabienne, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, GonzÃ¡lez-Neira, Anna, Greene, Mark H, GuÃ©nel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Hallberg, Emily, Hamann, Ute, and Hansen, Thomas V. O
Published: 2016

48. 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

49. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

Author: Easton, Douglas F, Lesueur, Fabienne, Decker, Brennan, Michailidou, Kyriaki, Li, Jun, Allen, Jamie, Luccarini, Craig, Pooley, Karen A, Shah, Mitul, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahmad, Jamil, Thompson, Ella R, Damiola, Francesca, Pertesi, Maroulio, Voegele, Catherine, Mebirouk, Noura, Robinot, Nivonirina, Durand, Geoffroy, Forey, Nathalie, Luben, Robert N, Ahmed, Shahana, Aittomäki, Kristiina, Anton-Culver, Hoda, Arndt, Volker, Australian Ovarian Cancer Study Group, Baynes, Caroline, Beckman, Matthias W, Benitez, Javier, Van Den Berg, David, Blot, William J, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Chang-Claude, Jenny, Chia, Kee Seng, Choi, Ji-Yeob, Conroy, Don M, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fostira, Florentia, García-Closas, Montserrat, Giles, Graham G, Glendon, Gord, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hart, Steven N, Hartman, Mikael, Hooning, Maartje J, Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, James, Paul A, John, Esther M, Johnson, Nichola, Jones, Michael, Kabisch, Maria, Kang, Daehee, kConFab Investigators, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Li, Na, Lifepool Investigators, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Meindl, Alfons, Mitchell, Gillian, Muir, Kenneth, NBCS Investigators, Nevelsteen, Ines, van den Ouweland, Ans, Peterlongo, Paolo, Phuah, Sze Yee, Pylkäs, Katri, Rowley, Simone M, Sangrajrang, Suleeporn, Schmutzler, Rita K, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony, and Teo, Soo H
Subjects: Australian Ovarian Cancer Study Group, kConFab Investigators, Lifepool Investigators, NBCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, RNA Helicases, DNA-Binding Proteins, Risk, Cohort Studies, Mutation, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Fanconi Anemia Complementation Group Proteins, Genetic Association Studies, Cancer: breast, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract: BACKGROUND:BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS:We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS:The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS:These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
Published: 2016

50. 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, Clinical Trials and Supportive Activities, Ovarian Cancer, Genetic Testing, Women's Health, Rare Diseases, Prevention, Breast Cancer, Genetics, Cancer, 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

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

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

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

1,279 results on '"Cross, Simon S."'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources