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

Author

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, Women's Health, Breast Cancer, Clinical Research, Prevention, Cancer, 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

2. 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

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

Author

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

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

BackgroundLow-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.MethodsWe evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.ResultsIn European ancestry samples, 14 genes were significantly associated (q

Published
2023

4. 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

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

Author

Morra, Anna, Escala-Garcia, Maria, Beesley, Jonathan, Keeman, Renske, Canisius, Sander, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Caan, Bette, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Ting-Yuan David, Clarke, Christine L, 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

6. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Author

Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, and Wolk, Alicja

Subjects
kConFab/AOCS Investigators, Cancer, Genetics, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies
Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Published
2021

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

Author

Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U., Antonenkova, Natalia N., Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J., Bogdanova, Natalia V., Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chanock, Stephen J., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine D., Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K., Ko, Yon-Dschun, Kristensen, Vessela N., Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Rashid, Muhammad U., Rhenius, Valerie, Rookus, Matti A., Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sironen, Reijo, Southey, Melissa C., Suvanto, Maija, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Thérèse, van der Kolk, Lizet E., van Veen, Elke M., Wappenschmidt, Barbara, Yang, Xiaohong R., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul D. P., Wang, Qin, Adank, Muriel A., Schmidt, Marjanka K., Andrulis, Irene L., Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D. Gareth, Milne, Roger L., Radice, Paolo, and Peterlongo, Paolo

Published
2023
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8. 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

9. The impact of coding germline variants on contralateral breast cancer risk and survival

Author

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

Published
2023
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10. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author

Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T., Fortuno, Cristina, González-Neira, Anna, Heijl, Stephan M., Adank, Muriel A., Ahearn, Thomas U., Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bremer, Michael, Briceno, Ignacio, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Collée, J. Margriet, Czene, Kamila, Dennis, Joe, Dörk, Thilo, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubiński, Jan, Luccarini, Craig, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G., Oosterwijk, Jan C., Park, Sue K., Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, van Asperen, Christi J., Waltes, Regina, Wang, Qin, Yang, Xiaohong R., Pharoah, Paul D. P., Schmidt, Marjanka K., Benitez, Javier, Vroling, Bas, Dunning, Alison M., Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B., Vreeswijk, Maaike P. G., and Easton, Douglas F.

Published
2022
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11. 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

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

Author

Augustinsson, Annelie, Augustinsson, Annelie, Beckmann, Matthias, Behrens, Sabine, Bojesen, Stig, Bolla, Manjeet, Brauch, Hiltrud, Broeks, Annegien, Buys, Saundra, Camp, Nicola, Castelao, Jose, Cessna, Melissa, Chang-Claude, Jenny, Chung, Wendy, Colonna, Sarah, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Daly, Mary, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison, Dwek, Miriam, Easton, Douglas, Eccles, Diana, Eriksson, Mikael, Evans, D, Fasching, Peter, Fehm, Tanja, Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José, Genkinger, Jeanine, Grassmann, Felix, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher, Hamann, Ute, Harrington, Patricia, Hartikainen, Jaana, Hoppe, Reiner, Hopper, John, Houlston, Richard, Howell, Anthony, Jakubowska, Anna, Janni, Wolfgang, Jernström, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Kristensen, Vessela, Kurian, Allison, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Lubiński, Jan, Lux, Michael, Mannermaa, Arto, Mavroudis, Dimitrios, Mulligan, Anna, Muranen, Taru, Nevanlinna, Heli, Nevelsteen, Ines, Neven, Patrick, Newman, William, Obi, Nadia, Offit, Kenneth, Olshan, Andrew, Park-Simon, Tjoung-Won, Patel, Alpa, Peterlongo, Paolo, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Polley, Eric, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad, Rhenius, Valerie, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor, Schmutzler, Rita, Schuetze, Sabine, Scott, Christopher, Shah, Mitul, Smichkoska, Snezhana, Southey, Melissa, Tapper, William, Teras, Lauren, Tollenaar, Rob, Tomczyk, Katarzyna, Tomlinson, Ian, Augustinsson, Annelie, Augustinsson, Annelie, Beckmann, Matthias, Behrens, Sabine, Bojesen, Stig, Bolla, Manjeet, Brauch, Hiltrud, Broeks, Annegien, Buys, Saundra, Camp, Nicola, Castelao, Jose, Cessna, Melissa, Chang-Claude, Jenny, Chung, Wendy, Colonna, Sarah, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Daly, Mary, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison, Dwek, Miriam, Easton, Douglas, Eccles, Diana, Eriksson, Mikael, Evans, D, Fasching, Peter, Fehm, Tanja, Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José, Genkinger, Jeanine, Grassmann, Felix, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher, Hamann, Ute, Harrington, Patricia, Hartikainen, Jaana, Hoppe, Reiner, Hopper, John, Houlston, Richard, Howell, Anthony, Jakubowska, Anna, Janni, Wolfgang, Jernström, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Kristensen, Vessela, Kurian, Allison, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Lubiński, Jan, Lux, Michael, Mannermaa, Arto, Mavroudis, Dimitrios, Mulligan, Anna, Muranen, Taru, Nevanlinna, Heli, Nevelsteen, Ines, Neven, Patrick, Newman, William, Obi, Nadia, Offit, Kenneth, Olshan, Andrew, Park-Simon, Tjoung-Won, Patel, Alpa, Peterlongo, Paolo, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Polley, Eric, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad, Rhenius, Valerie, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor, Schmutzler, Rita, Schuetze, Sabine, Scott, Christopher, Shah, Mitul, Smichkoska, Snezhana, Southey, Melissa, Tapper, William, Teras, Lauren, Tollenaar, Rob, Tomczyk, Katarzyna, and Tomlinson, Ian

Abstract

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

Published
2023

13. The impact of coding germline variants on contralateral breast cancer risk and survival

Author

Morra, Anna, Mavaddat, Nasim, Muranen, Taru A., Ahearn, Thomas U., Allen, Jamie, Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Behrens, Sabine, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Brauch, Hiltrud, Camp, Nicola J., Carvalho, Sara, Castelao, Jose E., Cessna, Melissa H., Chang-Claude, Jenny, Chenevix-Trench, Georgia, Sahlberg, Kristine K., Børresen-Dale, Anne Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Grenaker Alnæs, Grethe I., Czene, Kamila, Decker, Brennan, Dennis, Joe, Dörk, Thilo, Dorling, Leila, Dunning, Alison M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, Geurts-Giele, Willemina R.R., Giles, Graham G., Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Hall, Per, Hamann, Ute, Hooning, Maartje J., Morra, Anna, Mavaddat, Nasim, Muranen, Taru A., Ahearn, Thomas U., Allen, Jamie, Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Behrens, Sabine, Blomqvist, Carl, Bojesen, Stig E., Bolla, Manjeet K., Brauch, Hiltrud, Camp, Nicola J., Carvalho, Sara, Castelao, Jose E., Cessna, Melissa H., Chang-Claude, Jenny, Chenevix-Trench, Georgia, Sahlberg, Kristine K., Børresen-Dale, Anne Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Grenaker Alnæs, Grethe I., Czene, Kamila, Decker, Brennan, Dennis, Joe, Dörk, Thilo, Dorling, Leila, Dunning, Alison M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, Geurts-Giele, Willemina R.R., Giles, Graham G., Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Hall, Per, Hamann, Ute, and Hooning, Maartje J.

Abstract

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

Published
2023

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

Author

Billaud, Amandine, Figlioli, Gisella, Ahearn, Thomas U, Antonenkova, Natalia N, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J, Bogdanova, Natalia V, Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J, Campbell, Archie, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine D, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K, Ko, Yon-Dschun, Kristensen, Vessela N, Lindblom, Annika, Billaud, Amandine, Figlioli, Gisella, Ahearn, Thomas U, Antonenkova, Natalia N, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J, Bogdanova, Natalia V, Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J, Campbell, Archie, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine D, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K, Ko, Yon-Dschun, Kristensen, Vessela N, and Lindblom, Annika

Abstract

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

Published
2023

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

Author

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

Published
2023
Full Text
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17. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author

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

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

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

Published
2022
Full Text
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18. 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, 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, 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 L., Howell, Anthony, Hunter, David J., Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey Y., 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, Marchand, Loic Le, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Menon, Usha, Mulligan, Anna Marie, Murphy, Rachel A., Nevanlinna, Heli, Nevelsteen, Ines, Newman, William G., Offit, Kenneth, Olshan, Andrew F., Olsson, Håkan, Orr, Nick, Patel, Alpa V., Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rees-Punia, Erika, Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K, Schmutzler, Rita K., Schwentner, Lukas, Scott, Christopher, Shah, Mitul, Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Tollenaar, Rob A.E.M., Troester, Melissa A., Truong, Thérèse, Untch, Michael, Vachon, Celine M., Joseph, Vijai, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D.P., Easton, Douglas F., Milne, Roger L., Lynch, Brigid M., 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, 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, 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 L., Howell, Anthony, Hunter, David J., Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey Y., 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, Marchand, Loic Le, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Menon, Usha, Mulligan, Anna Marie, Murphy, Rachel A., Nevanlinna, Heli, Nevelsteen, Ines, Newman, William G., Offit, Kenneth, Olshan, Andrew F., Olsson, Håkan, Orr, Nick, Patel, Alpa V., Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rees-Punia, Erika, Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K, Schmutzler, Rita K., Schwentner, Lukas, Scott, Christopher, Shah, Mitul, Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Tollenaar, Rob A.E.M., Troester, Melissa A., Truong, Thérèse, Untch, Michael, Vachon, Celine M., Joseph, Vijai, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D.P., Easton, Douglas F., Milne, Roger L., and Lynch, Brigid M.

Abstract

Objectives Physical 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. Methods We 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 (n snps =5) or sedentary time (n snps =6), or accelerometer-measured (n snps =1) or self-reported (n snps =5) vigorous physical activity. Results Greater 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). Conclusion Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time a

Published
2022

19. Additional file 1 of Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author

Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T., Fortuno, Cristina, González-Neira, Anna, Heijl, Stephan M., Adank, Muriel A., Ahearn, Thomas U., Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bremer, Michael, Briceno, Ignacio, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Collée, J. Margriet, Czene, Kamila, Dennis, Joe, Dörk, Thilo, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubiński, Jan, Luccarini, Craig, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G., Oosterwijk, Jan C., Park, Sue K., Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, van Asperen, Christi J., Waltes, Regina, Wang, Qin, Yang, Xiaohong R., Pharoah, Paul D. P., Schmidt, Marjanka K., Benitez, Javier, Vroling, Bas, Dunning, Alison M., Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B., Vreeswijk, Maaike P. G., and Easton, Douglas F.

Subjects
Data_FILES
Abstract

Additional file 1.

Published
2022
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20. Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol

Author

Ziegler, Anette-Gabriele, primary, Arnolds, Stefanie, additional, Kölln, Annika, additional, Achenbach, Peter, additional, Berner, Reinhard, additional, Bonifacio, Ezio, additional, Casteels, Kristina, additional, Elding Larsson, Helena, additional, Gündert, Melanie, additional, Hasford, Joerg, additional, Kordonouri, Olga, additional, Lundgren, Markus, additional, Oltarzewski, Mariusz, additional, Pekalski, Marcin L, additional, Pfirrmann, Markus, additional, Snape, Matthew D, additional, Szypowska, Agnieszka, additional, and Todd, John A, additional

Published
2021
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21. FANCMmissense variants and breast cancer risk: a case-control association study of 75,156 European women

Author

Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U., Antonenkova, Natalia N., Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J., Bogdanova, Natalia V., Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chanock, Stephen J., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine D., Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K., Ko, Yon-Dschun, Kristensen, Vessela N., Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Rashid, Muhammad U., Rhenius, Valerie, Rookus, Matti A., Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sironen, Reijo, Southey, Melissa C., Suvanto, Maija, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Thérèse, van der Kolk, Lizet E., van Veen, Elke M., Wappenschmidt, Barbara, Yang, Xiaohong R., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul D. P., Wang, Qin, Adank, Muriel A., Schmidt, Marjanka K., Andrulis, Irene L., Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D. Gareth, Milne, Roger L., Radice, Paolo, and Peterlongo, Paolo

Abstract

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

Published
2023
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23. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol

Author

Ziegler, Anette-Gabriele, primary, Achenbach, Peter, additional, Berner, Reinhard, additional, Casteels, Kristina, additional, Danne, Thomas, additional, Gündert, Melanie, additional, Hasford, Joerg, additional, Hoffmann, Verena Sophia, additional, Kordonouri, Olga, additional, Lange, Karin, additional, Elding Larsson, Helena, additional, Lundgren, Markus, additional, Snape, Matthew D, additional, Szypowska, Agnieszka, additional, Todd, John A, additional, and Bonifacio, Ezio, additional

Published
2019
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24. Comparison of six breast cancer classifiers using qPCR

Author

Berchtold, Evi, primary, Vetter, Martina, additional, Gündert, Melanie, additional, Csaba, Gergely, additional, Fathke, Christine, additional, Ulbrich, Susanne E, additional, Thomssen, Christoph, additional, Zimmer, Ralf, additional, and Kantelhardt, Eva J, additional

Published
2019
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25. Evaluation of Promoter Methylation of RASSF1A and ATM in Peripheral Blood of Breast Cancer Patients and Healthy Control Individuals

Author

Cao, Xue, primary, Tang, Qiuqiong, additional, Holland-Letz, Tim, additional, Gündert, Melanie, additional, Cuk, Katarina, additional, Schott, Sarah, additional, Heil, Jörg, additional, Golatta, Michael, additional, Sohn, Christof, additional, Schneeweiss, Andreas, additional, and Burwinkel, Barbara, additional

Published
2018
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26. Genome-wide DNA methylation analysis reveals a prognostic classifier for non-metastatic colorectal cancer (ProMCol classifier)

Author

Gündert, Melanie, primary, Edelmann, Dominic, additional, Benner, Axel, additional, Jansen, Lina, additional, Jia, Min, additional, Walter, Viola, additional, Knebel, Phillip, additional, Herpel, Esther, additional, Chang-Claude, Jenny, additional, Hoffmeister, Michael, additional, Brenner, Hermann, additional, and Burwinkel, Barbara, additional

Published
2017
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27. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPADPOInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol.

Author

Ziegler, Anette-Gabriele, Achenbach, Peter, Berner, Reinhard, Casteels, Kristina, Danne, Thomas, Gündert, Melanie, Hasford, Joerg, Hoffmann, Verena Sophia, Kordonouri, Olga, Lange, Karin, Larsson, Helena Elding, Lundgren, Markus, Snape, Matthew D., Szypowska, Agnieszka, Todd, John A., and Bonifacio, Ezio

Abstract

Introduction The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes. Methods and analysis Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes. Ethics and dissemination The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. [ABSTRACT FROM AUTHOR]

Published
2019
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29. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author

Baxter, Joseph S, Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Brucker, Sara Y, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, NBCS Collaborators, Colonna, Sarah, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, García-Closas, Montserrat, García-Sáenz, José A, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hou, Ming-Feng, KConFab Investigators, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Larsson, Susanna C, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Jingmei, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Mayes, Rebecca, Menon, Usha, Milne, Roger L, Mohd Taib, Nur Aishah, Muir, Kenneth, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, O'Brien, Katie M, Offit, Kenneth, Olson, Janet E, Olsson, Håkan, Park, Sue K, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Rennert, Gad, Romero, Atocha, Ruebner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Southey, Melissa C, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teo, Soo Hwang, Teras, Lauren R, Terry, Mary Beth, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tseng, Chiu-Chen, Untch, Michael, Vachon, Celine M, Van Den Ouweland, Ans MW, Wang, Sophia S, Weinberg, Clarice R, Wendt, Camilla, Winham, Stacey J, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yamaji, Taiki, Zheng, Wei, Ziogas, Argyrios, Pharoah, Paul DP, Dunning, Alison M, Easton, Douglas F, Pettitt, Stephen J, Lord, Christopher J, Haider, Syed, Orr, Nick, and Fletcher, Olivia

Subjects
Chromosome Mapping, Genetic Variation, Breast Neoplasms, Molecular Sequence Annotation, functional annotation, 3. Good health, Cell Line, breast cancer risk, risk locus, Risk Factors, Chromosomes, Human, Pair 2, Humans, Female, CRISPR-Cas Systems, Insulin-Like Growth Factor Binding Protein 5, Promoter Regions, Genetic, Genetic Association Studies, Sequence Deletion
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).

30. 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 W. M., Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L., Mulligan, Anna Marie, Muranen, Taru A., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Olshan, Andrew F., Olsson, Håkan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V., Peissel, Bernard, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Rack, Brigitte, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schneeweiss, Andreas, Scott, Christopher, Shah, Mitul, Smichkoska, Snezhana, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teras, Lauren R., Terry, Mary Beth, Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Wang, Qin, Hurson, Amber N., Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Brauch, Hiltrud, García-Closas, Montserrat, Pharoah, Paul D. P., Easton, Douglas F., Chenevix-Trench, Georgia, Schmidt, Marjanka K., Børresen-Dale, Anne-Lise, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Grenaker Alnæs, Grethe I., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, J. Dinny, and Sachchithananthan, Mythily

Subjects
Tumor biology, Systemic treatment, Common germline genetic variants, Patient subgroups, 3. Good health, Research Article, Breast cancer-specific survival
Abstract

Funder: FP7 Ideas: European Research Council; doi: http://dx.doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, Background: Given 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. Methods: We 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 < 0.15). Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

31. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author

Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Couch, Fergus J., Czene, Kamila, Daly, Mary B., Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Easton, Douglas F., Ekici, Arif B., Eliassen, A. Heather, Fasching, Peter A., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Geisler, Jürgen, Giles, Graham G., Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M., Heemskerk-Gerritsen, Bernadette A. M., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Hunter, David J., Jacot, William, Jakubowska, Anna, John, Esther M., Jung, Audrey Y., Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B., Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N., Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A., Nevanlinna, Heli, Olshan, Andrew F., Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V., Peterlongo, Paolo, Pharoah, Paul D. P., Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Christopher, Southey, Melissa C., Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Teras, Lauren R., Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A., Vachon, Celine M., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Michailidou, Kyriaki, Chenevix-Trench, Georgia, Bachelot, Thomas, and Schmidt, Marjanka K.

Subjects
631/67/322, 631/67/68, article, 631/67/1347, skin and connective tissue diseases, 3. Good health
Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

32. Additional file 2 of 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 W. M., Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L., Mulligan, Anna Marie, Muranen, Taru A., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Olshan, Andrew F., Olsson, Håkan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V., Peissel, Bernard, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Rack, Brigitte, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schneeweiss, Andreas, Scott, Christopher, Shah, Mitul, Smichkoska, Snezhana, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teras, Lauren R., Terry, Mary Beth, Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Wang, Qin, Hurson, Amber N., Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Brauch, Hiltrud, García-Closas, Montserrat, Pharoah, Paul D. P., Easton, Douglas F., Chenevix-Trench, Georgia, and Schmidt, Marjanka K.

Subjects
3. Good health
Abstract

Additional file 2: Supplementary Methods, Supplementary Table S5, Supplementary Table S6, Supplementary Table S7, Supplementary Figure S1, Supplementary Figure S2, Supplementary Figure S3, Supplementary Figure S4, Supplementary Figure S5, Supplementary Figure S6, Supplementary Figure S7, Supplementary Figure S8, Supplementary Figure S9, Supplementary Figure S10, Supplementary Figure S11, Supplementary Figure S12. The Supplementary methods section includes details about: multiple imputation of missing data; power calculations. Supplementary Table S5. Shows an overview of number of breast cancer patients, breast cancer deaths and follow-up information by subgroup and endpoint. Supplementary Table S6. Shows a list of imputed variables with corresponding percentage of missing values, imputation method and processing. Supplementary Table S7. Shows an overview of the GWAS significant associations (P 5E-08) variants from the 15-year and 5-year genome-wide breast cancer-specific survival analyses. Supplementary Figure S7 shows the unadjusted association of variant rs5934618 with 15-year breast cancer-specific survival by tumor grade and in all breast cancer patients. Supplementary Figure S8. Shows the functional annotation and position of variants rs5934618, rs4830644, rs3810742, rs4830642, and rs72611496 relative to TBL1X. Supplementary Figure S9. Shows Kaplan-Meier distant metastasis-free survival plots (based on KMPlotter data) for high versus low expression level of gene TBL1X by tumor grade. Supplementary Figure S10. Shows the association of genetic variants with TBL1X expression, based on GTEx v8 data on samples of normal breast tissue from 396 individuals (male and female). Supplementary Figure S11. Shows a Kaplan-Meier distant metastasis-free survival plot for high versus low expression level of gene GRIP2, restricted to patients with an ER- tumor who received chemotherapy (based on KMPlotter data). Supplementary Figure S12. Shows a Kaplan-Meier distant metastasis-free survival plot for high versus low expression level of gene ARAP2, restricted to patients with an ER- tumor who received chemotherapy (based on KMPlotter data).

33. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author

Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, KConFab/AOCS Investigators, Michailidou, Kyriaki, Chenevix-Trench, Georgia, Bachelot, Thomas, and Schmidt, Marjanka K

Subjects
Germ Cells, Cancer Survivors, Biomarkers, Tumor, Genetic Variation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Kaplan-Meier Estimate, skin and connective tissue diseases, Polymorphism, Single Nucleotide, Germ-Line Mutation, 3. Good health
Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

34. Additional file 2 of 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 W. M., Martinez, Maria Elena, Mavroudis, Dimitrios, Michailidou, Kyriaki, Milne, Roger L., Mulligan, Anna Marie, Muranen, Taru A., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Olshan, Andrew F., Olsson, Håkan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V., Peissel, Bernard, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Rack, Brigitte, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schneeweiss, Andreas, Scott, Christopher, Shah, Mitul, Smichkoska, Snezhana, Southey, Melissa C., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teras, Lauren R., Terry, Mary Beth, Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Wang, Qin, Hurson, Amber N., Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Brauch, Hiltrud, García-Closas, Montserrat, Pharoah, Paul D. P., Easton, Douglas F., Chenevix-Trench, Georgia, and Schmidt, Marjanka K.

Subjects
3. Good health
Abstract

Additional file 2: Supplementary Methods, Supplementary Table S5, Supplementary Table S6, Supplementary Table S7, Supplementary Figure S1, Supplementary Figure S2, Supplementary Figure S3, Supplementary Figure S4, Supplementary Figure S5, Supplementary Figure S6, Supplementary Figure S7, Supplementary Figure S8, Supplementary Figure S9, Supplementary Figure S10, Supplementary Figure S11, Supplementary Figure S12. The Supplementary methods section includes details about: multiple imputation of missing data; power calculations. Supplementary Table S5. Shows an overview of number of breast cancer patients, breast cancer deaths and follow-up information by subgroup and endpoint. Supplementary Table S6. Shows a list of imputed variables with corresponding percentage of missing values, imputation method and processing. Supplementary Table S7. Shows an overview of the GWAS significant associations (P 5E-08) variants from the 15-year and 5-year genome-wide breast cancer-specific survival analyses. Supplementary Figure S7 shows the unadjusted association of variant rs5934618 with 15-year breast cancer-specific survival by tumor grade and in all breast cancer patients. Supplementary Figure S8. Shows the functional annotation and position of variants rs5934618, rs4830644, rs3810742, rs4830642, and rs72611496 relative to TBL1X. Supplementary Figure S9. Shows Kaplan-Meier distant metastasis-free survival plots (based on KMPlotter data) for high versus low expression level of gene TBL1X by tumor grade. Supplementary Figure S10. Shows the association of genetic variants with TBL1X expression, based on GTEx v8 data on samples of normal breast tissue from 396 individuals (male and female). Supplementary Figure S11. Shows a Kaplan-Meier distant metastasis-free survival plot for high versus low expression level of gene GRIP2, restricted to patients with an ER- tumor who received chemotherapy (based on KMPlotter data). Supplementary Figure S12. Shows a Kaplan-Meier distant metastasis-free survival plot for high versus low expression level of gene ARAP2, restricted to patients with an ER- tumor who received chemotherapy (based on KMPlotter data).

35. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana. Grupo de investigación Instituto de Genética Humana, Briceño Balcázar, Ignacio, Torres-López, Diana María, Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T., Fortuno, Cristina, González-Neira, Anna, Heijl, Stephan M., Adank, Muriel A., Ahearn, Thomas U., Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bremer, Michael, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, NBCS Collaborators, Collée, J. Margriet, Czene, Kamila, Dennis, Joe, Dörk, Thilo, Eriksson, Mikael, Evans, Gareth D., Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, kConFab Investigators, SGBCC Investigators, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubiński, Jan, Luccarini, Craig, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G., Oosterwijk, Jan C., Park, Sue K., Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Truong, Thérèse, van Asperen, Christi J., Waltes, Regina, Wang, Qin, Yang, Xiaohong R., Pharoah, Paul D. P., Schmidt, Marjanka K., Benitez, Javier, Vroling, Bas, Dunning, Alison M., Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B., Vreeswijk, Maaike P.G., Easton, Douglas F., Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana. Grupo de investigación Instituto de Genética Humana, Briceño Balcázar, Ignacio, Torres-López, Diana María, Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T., Fortuno, Cristina, González-Neira, Anna, Heijl, Stephan M., Adank, Muriel A., Ahearn, Thomas U., Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bremer, Michael, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, NBCS Collaborators, Collée, J. Margriet, Czene, Kamila, Dennis, Joe, Dörk, Thilo, Eriksson, Mikael, Evans, Gareth D., Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, kConFab Investigators, SGBCC Investigators, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubiński, Jan, Luccarini, Craig, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G., Oosterwijk, Jan C., Park, Sue K., Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Truong, Thérèse, van Asperen, Christi J., Waltes, Regina, Wang, Qin, Yang, Xiaohong R., Pharoah, Paul D. P., Schmidt, Marjanka K., Benitez, Javier, Vroling, Bas, Dunning, Alison M., Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B., Vreeswijk, Maaike P.G., and Easton, Douglas F.

36. The impact of coding germline variants on contralateral breast cancer risk and survival.

Author

Morra A, Mavaddat N, Muranen TA, Ahearn TU, Allen J, Andrulis IL, Auvinen P, Becher H, Behrens S, Blomqvist C, Bojesen SE, Bolla MK, Brauch H, Camp NJ, Carvalho S, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, Czene K, Decker B, Dennis J, Dörk T, Dorling L, Dunning AM, Ekici AB, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Geurts-Giele WRR, Giles GG, Guénel P, Gündert M, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Heikkilä P, Hooning MJ, Hoppe R, Howell A, Humphreys K, Jakubowska A, Jung AY, Keeman R, Kristensen VN, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Mavroudis D, Milne RL, Mulligan AM, Newman WG, Park-Simon TW, Peterlongo P, Pharoah PDP, Rhenius V, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Spurdle AB, Tomlinson I, Truong T, van Veen EM, Vreeswijk MPG, Wang Q, Wendt C, Yang XR, Nevanlinna H, Devilee P, Easton DF, and Schmidt MK

Subjects
Female, Humans, Genes, BRCA2, Germ-Line Mutation, Germ Cells, Genetic Predisposition to Disease, Breast Neoplasms genetics
Abstract

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis., Competing Interests: Declaration of interests B.D. is a stockholder of Roche, Vaccitech and EQRx. P.A.F. conducts research funded by Amgen, Novartis, and Pfizer outside the submitted work. He received honoraria from Roche, Novartis, and Pfizer outside the submitted work. D.F.E. is an associate editor at The American Journal of Human Genetics (AJHG)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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37. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Author

Morra A, Schreurs MAC, Andrulis IL, Anton-Culver H, Augustinsson A, Beckmann MW, Behrens S, Bojesen SE, Bolla MK, Brauch H, Broeks A, Buys SS, Camp NJ, Castelao JE, Cessna MH, Chang-Claude J, Chung WK, Collaborators N, Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Dennis J, Devilee P, Dörk T, Dunning AM, Dwek M, Easton DF, Eccles DM, Eriksson M, Evans DG, Fasching PA, Fehm TN, Figueroa JD, Flyger H, Gabrielson M, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Genkinger J, Grassmann F, Gündert M, Hahnen E, Haiman CA, Hamann U, Harrington PA, Hartikainen JM, Hoppe R, Hopper JL, Houlston RS, Howell A, Investigators A, Investigators K, Jakubowska A, Janni W, Jernström H, John EM, Johnson N, Jones ME, Kristensen VN, Kurian AW, Lambrechts D, Marchand LL, Lindblom A, Lubiński J, Lux MP, Mannermaa A, Mavroudis D, Mulligan AM, Muranen TA, Nevanlinna H, Nevelsteen I, Neven P, Newman WG, Obi N, Offit K, Olshan AF, Park-Simon TW, Patel AV, Peterlongo P, Phillips KA, Plaseska-Karanfilska D, Polley EC, Presneau N, Pylkäs K, Rack B, Radice P, Rashid MU, Rhenius V, Robson M, Romero A, Saloustros E, Sawyer EJ, Schmutzler RK, Schuetze S, Scott C, Shah M, Smichkoska S, Southey MC, Tapper WJ, Teras LR, Tollenaar RAEM, Tomczyk K, Tomlinson I, Troester MA, Vachon CM, van Veen EM, Wang Q, Wendt C, Wildiers H, Winqvist R, Ziogas A, Hall P, Pharoah PDP, Adank MA, Hollestelle A, Schmidt MK, and Hooning MJ

Abstract

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of 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. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).

Published
2023
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