Author: "Beesley, Jonathan" - Searchworks@Jio Institute Digital Library Search Results

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1. Distinct roles of SOX9 in self-renewal of progenitors and mesenchymal transition of the endothelium

Author: Zhao, Jilai, Sormani, Laura, Jacquelin, Sebastien, Li, Haiming, Styke, Cassandra, Zhou, Chenhao, Beesley, Jonathan, Oon, Linus, Kaur, Simranpreet, Sim, Seen-Ling, Wong, Ho Yi, Dight, James, Hashemi, Ghazaleh, Shafiee, Abbas, Roy, Edwige, Patel, Jatin, and Khosrotehrani, Kiarash
Published: 2024
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2. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

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

3. Ultra-relativistic thermal production of electrons and positrons

Author: Beesley, Jonathan Jacob and Rose, Steven
Abstract: This thesis investigates ultra-relativistic processes of thermal production of electrons and positrons, and the theories involved in their description. It first focuses on collisional ionisation and excitation rates in a partially-ionised plasma, presenting correction factors to them that account for special relativity in the free electron motion as a function of temperature and the threshold energy. These results are extended to de-excitation and three body recombination using detailed balance. It then turns to the production of electron-positron pairs from Breit-Wheeler two-photon collision in the black-body field, and presents an analytic expression for the high-temperature limit of the total rate. It then examines the same physical process using the formalism of "external fields", in which the black-body is treated as as a thermal ensemble of classical field profiles. It presents a novel formal scheme for this calculation, and then presents the results of a numerical scheme that approximates this field ensemble by 1D spatial "Sauter pulses". It is found that pair-production calculated by this means exceeds that calculated by Breit-Wheeler by a large factor, and the energy spectrum of produced particles is presented. Then, work comparing different theoretical formalisms of vacuum-destabilising background fields in QED is presented. It is first shown how solving the Dirac equation with peculiar boundary conditions can give probability amplitudes for fermion scattering and pair creation/annihilation. It is then demonstrated for a broad class of external fields that four fermion propagators used in the literature are equivalent: Schwinger's "proper-time" propagator; the "causal propagator" used in the "Bogoliubov transformation" method; and two defined using analytic continuation. To do so, we re-derive Schwinger's proper-time expression for the propagator as a statement relating solutions of the inhomogeneous Dirac equation to those of the inhomogeneous "proper-time Dirac equation". We then show that all four propagators return solutions of the inhomogeneous Dirac equation that satisfy the same boundary condition.
Published: 2023
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4. CRISPR screens identify gene targets at breast cancer risk loci

Author: Tuano, Natasha K., Beesley, Jonathan, Manning, Murray, Shi, Wei, Perlaza-Jimenez, Laura, Malaver-Ortega, Luis F., Paynter, Jacob M., Black, Debra, Civitarese, Andrew, McCue, Karen, Hatzipantelis, Aaron, Hillman, Kristine, Kaufmann, Susanne, Sivakumaran, Haran, Polo, Jose M., Reddel, Roger R., Band, Vimla, French, Juliet D., Edwards, Stacey L., Powell, David R., Chenevix-Trench, Georgia, and Rosenbluh, Joseph
Published: 2023
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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. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author: Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Edwards, Digna R Velez, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Group, for the AGO Study, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Group, for the OPAL Study, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Group, for Australian Ovarian Cancer Study, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, and Chenevix-Trench, Georgia
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Human Genome, Cancer, Genetics, Ovarian Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Autophagy-Related Protein-1 Homolog, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Female, Gene Knockout Techniques, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Progression-Free Survival, AGO Study Group, OPAL Study Group, for Australian Ovarian Cancer Study Group, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.
Published: 2021

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

Author: Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, and Hopper, John L
Subjects: GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Cancer
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

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

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

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

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

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

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

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

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

13. 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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14. Pooled genetic screens identify breast cancer risk genes involved in evasion from T cell-mediated killing

Author: Shi, Wei, primary, Luo, Yi, additional, Burrows, Jacqueline M., additional, Black, Debra, additional, Civitarese, Andrew, additional, Perlaza-Jimenez, Laura, additional, Ping, Zhang, additional, Manning, Murray, additional, Tuano, Natasha, additional, Renteria, Miguel E., additional, Xiao, Christos, additional, Tey, Siok-Keen, additional, Rosenbluh, Joseph, additional, Smith, Corey, additional, Chenevix-Trench, Georgia, additional, and Beesley, Jonathan, additional
Published: 2024
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15. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, and Holleczek, Bernd
Subjects: NBCS Collaborators, Chromosomes, Human, Pair 7, Humans, Breast Neoplasms, Receptors, Estrogen, Prognosis, Proportional Hazards Models, Bayes Theorem, Female, Genetic Variation, Genome-Wide Association Study, White People, Genetics, Breast Cancer, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P
Published: 2019

16. Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Author: Saunus, Jodi M., De Luca, Xavier M., Northwood, Korinne, Raghavendra, Ashwini, Hasson, Alexander, McCart Reed, Amy E., Lim, Malcolm, Lal, Samir, Vargas, A. Cristina, Kutasovic, Jamie R., Dalley, Andrew J., Miranda, Mariska, Kalaw, Emarene, Kalita-de Croft, Priyakshi, Gresshoff, Irma, Al-Ejeh, Fares, Gee, Julia M. W., Ormandy, Chris, Khanna, Kum Kum, Beesley, Jonathan, Chenevix-Trench, Georgia, Green, Andrew R., Rakha, Emad A., Ellis, Ian O., Nicolau, Jr, Dan V., Simpson, Peter T., and Lakhani, Sunil R.
Published: 2022
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17. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author: Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, and Huang, Guanmengqian
Subjects: Biological Sciences, Genetics, Cancer, Breast Cancer, Human Genome, Prevention, Women's Health, Cancer Genomics, Biotechnology, 2.1 Biological and endogenous factors, Generic health relevance, Breast Neoplasms, Case-Control Studies, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk, Transcriptome, NBCS Collaborators, kConFab/AOCS Investigators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P
Published: 2018

18. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Author: Ghoussaini, Maya, Edwards, Stacey L, Michailidou, Kyriaki, Nord, Silje, Cowper-Sal Lari, Richard, Desai, Kinjal, Kar, Siddhartha, Hillman, Kristine M, Kaufmann, Susanne, Glubb, Dylan M, Beesley, Jonathan, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Guo, Qi, Schmidt, Marjanka K, Shah, Mitul, Luben, Robert, Brown, Judith, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Klevebring, Daniel, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Lambrechts, Diether, Thienpont, Bernard, Neven, Patrick, Wildiers, Hans, Broeks, Annegien, Van't Veer, Laura J, Rutgers, Emiel J Th, Couch, Fergus J, Olson, Janet E, Hallberg, Emily, Vachon, Celine, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, Dos-Santos-Silva, Isabel, Gibson, Lorna, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K, Noh, Dong-Young, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Benitez, Javier, Pilar Zamora, M, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Qiuyin, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Lindblom, Annika, Margolin, Sara, and Teo, Soo Hwang
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

19. Correction: Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author: Ghoussaini, Maya, Edwards, Stacey L, Michailidou, Kyriaki, Nord, Silje, Cowper-Sal·lari, Richard, Desai, Kinjal, Kar, Siddhartha, Hillman, Kristine M, Kaufmann, Susanne, Glubb, Dylan M, Beesley, Jonathan, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Guo, Qi, Schmidt, Marjanka K, Shah, Mitul, Luben, Robert, Brown, Judith, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Klevebring, Daniel, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Lambrechts, Diether, Thienpont, Bernard, Neven, Patrick, Wildiers, Hans, Broeks, Annegien, Van’t Veer, Laura J, Rutgers, Emiel J Th, Couch, Fergus J, Olson, Janet E, Hallberg, Emily, Vachon, Celine, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, dos-Santos-Silva, Isabel, Gibson, Lorna, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K, Noh, Dong-Young, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Wu, Anna H, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O, Benitez, Javier, Pilar Zamora, M, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Qiuyin, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Lindblom, Annika, Margolin, Sara, and Teo, Soo Hwang
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

20. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology

Author: Ferreira, Manuel A, Vonk, Judith M, Baurecht, Hansjörg, Marenholz, Ingo, Tian, Chao, Hoffman, Joshua D, Helmer, Quinta, Tillander, Annika, Ullemar, Vilhelmina, van Dongen, Jenny, Lu, Yi, Rüschendorf, Franz, Esparza-Gordillo, Jorge, Medway, Chris W, Mountjoy, Edward, Burrows, Kimberley, Hummel, Oliver, Grosche, Sarah, Brumpton, Ben M, Witte, John S, Hottenga, Jouke-Jan, Willemsen, Gonneke, Zheng, Jie, Rodríguez, Elke, Hotze, Melanie, Franke, Andre, Revez, Joana A, Beesley, Jonathan, Matheson, Melanie C, Dharmage, Shyamali C, Bain, Lisa M, Fritsche, Lars G, Gabrielsen, Maiken E, Balliu, Brunilda, Nielsen, Jonas B, Zhou, Wei, Hveem, Kristian, Langhammer, Arnulf, Holmen, Oddgeir L, Løset, Mari, Abecasis, Gonçalo R, Willer, Cristen J, Arnold, Andreas, Homuth, Georg, Schmidt, Carsten O, Thompson, Philip J, Martin, Nicholas G, Duffy, David L, Novak, Natalija, Schulz, Holger, Karrasch, Stefan, Gieger, Christian, Strauch, Konstantin, Melles, Ronald B, Hinds, David A, Hübner, Norbert, Weidinger, Stephan, Magnusson, Patrik KE, Jansen, Rick, Jorgenson, Eric, Lee, Young-Ae, Boomsma, Dorret I, Almqvist, Catarina, Karlsson, Robert, Koppelman, Gerard H, and Paternoster, Lavinia
Subjects: Biological Sciences, Genetics, Emerging Infectious Diseases, Lung, Prevention, Asthma, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Eczema, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypersensitivity, Phenotype, Polymorphism, Single Nucleotide, Rhinitis, Allergic, Seasonal, Risk Factors, 23andMe Research Team, AAGC collaborators, BIOS consortium, LifeLines Cohort Study, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
Published: 2017

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

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

22. Association analysis identifies 65 new breast cancer risk loci

Author: Michailidou, Kyriaki, Lindström, Sara, Dennis, Joe, Beesley, Jonathan, Hui, Shirley, Kar, Siddhartha, Lemaçon, Audrey, Soucy, Penny, Glubb, Dylan, Rostamianfar, Asha, Bolla, Manjeet K, Wang, Qin, Tyrer, Jonathan, Dicks, Ed, Lee, Andrew, Wang, Zhaoming, Allen, Jamie, Keeman, Renske, Eilber, Ursula, French, Juliet D, Qing Chen, Xiao, Fachal, Laura, McCue, Karen, McCart Reed, Amy E, Ghoussaini, Maya, Carroll, Jason S, Jiang, Xia, Finucane, Hilary, Adams, Marcia, Adank, Muriel A, Ahsan, Habibul, Aittomäki, Kristiina, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Arun, Banu, Auer, Paul L, Bacot, François, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith S, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Butterbach, Katja, Cai, Qiuyin, Cai, Hui, Caldés, Trinidad, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chan, Tsun L, David Cheng, Ting-Yuan, Seng Chia, Kee, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Collée, Margriet, Conroy, Don M, Cordina-Duverger, Emilie, Cornelissen, Sten, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Elvira, Mingajeva, and Engel, Christoph
Subjects: Cancer, Asia, Asian People, Binding Sites, Breast Neoplasms, Computer Simulation, Europe, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors, White People, NBCS Collaborators, ABCTB Investigators, ConFab/AOCS Investigators, General Science & Technology
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Published: 2017

23. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author: Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja KH, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, AOCS study group, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, and Dorfling, Cecilia M
Subjects: AOCS study group, EMBRACE Study, GEMO Study Collaborators, HEBON Study, KConFab Investigators, OPAL study group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Telomere-Binding Proteins, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Mutation, Polymorphism, Single Nucleotide, Alleles, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Carcinoma, Ovarian Epithelial, Genetics, Cancer, Human Genome, Rare Diseases, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Published: 2017

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

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

25. On the Equivalence of Causal Propagators of the Dirac Equation in Vacuum-Destabilising External Fields

Author: Beesley, Jonathan J.
Published: 2022
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26. Immune Cell Associations with Cancer Risk

Author: Palomero, Luis, Galván-Femenía, Ivan, de Cid, Rafael, Espín, Roderic, Barnes, Daniel R., CIMBA, Blommaert, Eline, Gil-Gil, Miguel, Falo, Catalina, Stradella, Agostina, Ouchi, Dan, Roso-Llorach, Albert, Violan, Concepció, Peña-Chilet, María, Dopazo, Joaquín, Extremera, Ana Isabel, García-Valero, Mar, Herranz, Carmen, Mateo, Francesca, Mereu, Elisabetta, Beesley, Jonathan, Chenevix-Trench, Georgia, Roux, Cecilia, Mak, Tak, Brunet, Joan, Hakem, Razq, Gorrini, Chiara, Antoniou, Antonis C., Lázaro, Conxi, and Pujana, Miquel Angel
Published: 2020
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27. Fine‐scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

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

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

Author: Darabi, Hatef, Beesley, Jonathan, and Kar, Siddhartha
Published: 2016

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

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

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

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

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

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

32. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

Author: French, Juliet D, Johnatty, Sharon E, Lu, Yi, Beesley, Jonathan, Gao, Bo, Kalimutho, Murugan, Henderson, Michelle J, Russell, Amanda J, Kar, Siddhartha, Chen, Xiaoqing, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, O’Reilly, Martin, Wang, Chen, Korbie, Darren J, Group, Australian Ovarian Cancer Study, Study, Australian Cancer, Lambrechts, Diether, Despierre, Evelyn, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Pisterer, Jacobus, Hillemanns, Peter, Nakanishi, Toru, Yatabe, Yasushi, Goodman, Marc T, Lurie, Galina, Matsuno, Rayna K, Thompson, Pamela J, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James M, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen M, Iversen, Ed, Weber, Rachel Palmieri, Brennan, Donal, Berchuck, Andrew, Pharoah, Paul, Harnett, Paul, Norris, Murray D, Haber, Michelle, Goode, Ellen L, Lee, Jason S, Khanna, Kum Kum, Meyer, Kerstin B, Chenevix-Trench, Georgia, deFazio, Anna, Edwards, Stacey L, MacGregor, Stuart, and Consortium, on behalf of the Ovarian Cancer Association
Subjects: Genetics, Rare Diseases, Human Genome, Ovarian Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Cohort Studies, Cystadenocarcinoma, Serous, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Fallopian Tube Neoplasms, Female, Follow-Up Studies, Germ-Line Mutation, Humans, Ovarian Neoplasms, Peritoneal Neoplasms, Polymorphism, Single Nucleotide, Prognosis, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Transcription Factors, Tumor Cells, Cultured, epithelial ovarian cancer, progression free survival, genome-wide association study, PSIP1, chromosome conformation capture, Australian Ovarian Cancer Study Group, Australian Ovarian Cancer Study, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis
Abstract: Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
Published: 2016

33. Evidence of a genetic link between endometriosis and ovarian cancer

Author: Lee, Alice W, Templeman, Claire, Stram, Douglas A, Beesley, Jonathan, Tyrer, Jonathan, Berchuck, Andrew, Pharoah, Paul P, Chenevix-Trench, Georgia, Pearce, Celeste Leigh, Consortium, Ovarian Cancer Association, Ness, Roberta B, Dansonka-Mieszkowska, Agnieszka, Gentry-Maharaj, Aleksandra, Hein, Alexander, Whittemore, Alice S, Jensen, Allan, du Bois, Andreas, Brooks-Wilson, Angela, Rudolph, Anja, Jakubowska, Anna, Wu, Anna H, Ziogas, Argyrios, Ekici, Arif B, Leminen, Arto, Study, Australian Cancer, Group, Australian Ovarian Cancer Study, Rosen, Barry, Spiewankiewicz, Beata, Karlan, Beth Y, Trabert, Britton, Fridley, Brooke L, Gilks, C Blake, Krakstad, Camilla, Phelan, Catherine M, Cybulski, Cezary, Walsh, Christine, Hogdall, Claus, Cramer, Daniel W, Huntsman, David G, Eccles, Diana, Lambrechts, Diether, Liang, Dong, Levine, Douglas A, Iversen, Edwin S, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Van Nieuwenhuysen, Els, Hogdall, Estrid, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Giles, Graham G, Risch, Harvey A, Baker, Helen, Salvesen, Helga B, Nevanlinna, Heli, Anton-Culver, Hoda, Song, Honglin, McNeish, Iain, Campbell, Ian G, Vergote, Ignace, Runnebaum, Ingo B, Tangen, Ingvild L, Schwaab, Ira, Gronwald, Jacek, Paul, James, Lubinski, Jan, Doherty, Jennifer A, Chang-Claude, Jenny, Lester, Jenny, Schildkraut, Joellen M, McLaughlin, John R, Lissowska, Jolanta, Kupryjanczyk, Jolanta, Kelley, Joseph L, Rothstein, Joseph H, Cunningham, Julie M, Lu, Karen, Carty, Karen, Terry, Kathryn L, Aben, Katja KH, Moysich, Kirsten B, Wicklund, Kristine G, Odunsi, Kunle, Kiemeney, Lambertus A, Sucheston-Campbell, Lara, Lundvall, Lene, Massuger, Leon FAG, Pelttari, Liisa M, Kelemen, Linda E, Cook, Linda S, Bjorge, Line, Nedergaard, Lotte, Brinton, Louise A, Wilkens, Lynne R, Pike, Malcolm C, Goodman, Marc T, and Bisogna, Maria
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Cancer, Rare Diseases, Ovarian Cancer, Genetics, Genetic Testing, Clinical Research, Endometriosis, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Computational Biology, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasm Grading, Ovarian Neoplasms, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Ovarian Cancer Association Consortium, SNPs, genetic variation, ovarian cancer, Clinical Sciences, Paediatrics and Reproductive Medicine, Public Health and Health Services, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract: ObjectiveTo evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer.DesignPooled genetic analysis.SettingUniversity hospital.Patient(s)Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies.Intervention(s)None.Main outcome measure(s)Endometriosis-associated genetic variation and ovarian cancer.Result(s)There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected.Conclusion(s)By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Published: 2016

34. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Author: Vigorito, Elena, Kuchenbaecker, Karoline B, Beesley, Jonathan, Adlard, Julian, Agnarsson, Bjarni A, Andrulis, Irene L, Arun, Banu K, Barjhoux, Laure, Belotti, Muriel, Benitez, Javier, Berger, Andreas, Bojesen, Anders, Bonanni, Bernardo, Brewer, Carole, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chan, Salina B, Claes, Kathleen BM, Cohn, David E, Cook, Jackie, Daly, Mary B, Damiola, Francesca, Davidson, Rosemarie, Pauw, Antoine de, Delnatte, Capucine, Diez, Orland, Domchek, Susan M, Dumont, Martine, Durda, Katarzyna, Dworniczak, Bernd, Easton, Douglas F, Eccles, Diana, Edwinsdotter Ardnor, Christina, Eeles, Ros, Ejlertsen, Bent, Ellis, Steve, Evans, D Gareth, Feliubadalo, Lidia, Fostira, Florentia, Foulkes, William D, Friedman, Eitan, Frost, Debra, Gaddam, Pragna, Ganz, Patricia A, Garber, Judy, Garcia-Barberan, Vanesa, Gauthier-Villars, Marion, Gehrig, Andrea, Gerdes, Anne-Marie, Giraud, Sophie, Godwin, Andrew K, Goldgar, David E, Hake, Christopher R, Hansen, Thomas VO, Healey, Sue, Hodgson, Shirley, Hogervorst, Frans BL, Houdayer, Claude, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jacobs, Lauren, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, Jensen, Uffe Birk, John, Esther M, Vijai, Joseph, Karlan, Beth Y, Kast, Karin, KConFab Investigators, Khan, Sofia, Kwong, Ava, Laitman, Yael, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lubinski, Jan, Mai, Phuong L, Manoukian, Siranoush, Mazoyer, Sylvie, Meindl, Alfons, Mensenkamp, Arjen R, Montagna, Marco, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Ong, Kai-Ren, Osorio, Ana, Park, Sue Kyung, Paulsson-Karlsson, Ylva, Pedersen, Inge Sokilde, Peissel, Bernard, and Peterlongo, Paolo
Subjects: KConFab Investigators, Chromosomes, Human, Pair 9, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Chromosome Mapping, Polymorphism, Single Nucleotide, Genes, BRCA1, Genes, BRCA2, Female, Genetic Carrier Screening, General Science & Technology
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
Published: 2016

35. Distinct roles of SOX9 in self-renewal of progenitors and mesenchymal transition of the endothelium

Author: Zhao, Jilai, primary, Sormani, Laura, additional, Jacquelin, Sebastien, additional, Styke, Cassandra, additional, Zhou, Chenhao, additional, Beesley, Jonathan, additional, Oon, Linus, additional, Kaur, Simranpreet, additional, Sim, Seen-Ling, additional, Wong, Ho Yi, additional, Dight, James, additional, Hashemi, Ghazaleh, additional, Shafiee, Abbas, additional, Roy, Edwige, additional, Patel, Jatin, additional, and Khosrotehrani, Kiarash, additional
Published: 2023
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36. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author: Johnatty, Sharon E, Group, on behalf of the Australian Ovarian Cancer Study, Tyrer, Jonathan P, Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Levine, Douglas A, Kiemeney, Lambertus A, Massuger, Leon FAG, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S, McGuire, Valerie, Rothstein, Joseph H, Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O, Wu, Anna H, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K, Spiewankiewicz, Beata, Goodman, Marc T, Wilkens, Lynne R, Carney, Michael E, Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Group, on behalf of the AGO Study, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C, Fogarty, Zachary C, Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L, Cunningham, Julie M, Vierkant, Robert A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, and Pharoah, Paul DP
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Genetics, Human Genome, Precision Medicine, Rare Diseases, Women's Health, Cancer Genomics, Ovarian Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Alleles, Carcinoma, Ovarian Epithelial, Computational Biology, Female, Genome-Wide Association Study, Genotype, Humans, Kaplan-Meier Estimate, Meta-Analysis as Topic, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, AGO Study Group, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract: PurposeChemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental designWe analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.ResultsFive SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).ConclusionsWe have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.
Published: 2015

37. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

Author: Kelemen, Linda E, Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M, Seo, Ji-Heui, Phelan, Catherine M, Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chen, Y Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Doerk, Thilo, du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Engelholm, Svend Aage, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moysich, Kirsten B, Narod, Steven A, and Nedergaard, Lotte
Subjects: Developmental Biology, Medical and Health Sciences, Biological Sciences
Published: 2015

38. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Author: Darabi, Hatef, McCue, Karen, Beesley, Jonathan, Michailidou, Kyriaki, Nord, Silje, Kar, Siddhartha, Humphreys, Keith, Thompson, Deborah, Ghoussaini, Maya, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Canisius, Sander, Scott, Christopher G, Apicella, Carmel, Hopper, John L, Southey, Melissa C, Stone, Jennifer, Broeks, Annegien, Schmidt, Marjanka K, Scott, Rodney J, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Ekici, Arif B, Fasching, Peter A, Heusinger, Katharina, dos-Santos-Silva, Isabel, Peto, Julian, Tomlinson, Ian, Sawyer, Elinor J, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Anton-Culver, Hoda, Neuhausen, Susan L, Arndt, Volker, Brenner, Hermann, Engel, Christoph, Meindl, Alfons, Schmutzler, Rita K, Cancer, German Consortium of Hereditary Breast and Ovarian, Arnold, Norbert, Brauch, Hiltrud, Hamann, Ute, Chang-Claude, Jenny, Khan, Sofia, Nevanlinna, Heli, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natalia V, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Investigators, kConFab AOCS, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-chen, Wu, Anna H, Floris, Giuseppe, Lambrechts, Diether, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Couch, Fergus J, Vachon, Celine, Giles, Graham G, McLean, Catriona, Milne, Roger L, Dugué, Pierre-Antoine, Haiman, Christopher A, Maskarinec, Gertraud, Woolcott, Christy, Henderson, Brian E, Goldberg, Mark S, Simard, Jacques, Teo, Soo H, Mariapun, Shivaani, Helland, Åslaug, Haakensen, Vilde, Zheng, Wei, Beeghly-Fadiel, Alicia, Tamimi, Rulla, Jukkola-Vuorinen, Arja, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Tollenaar, Robert AEM, Figueroa, Jonine, García-Closas, Montserrat, Czene, Kamila, Hooning, Maartje J, Tilanus-Linthorst, Madeleine, and Li, Jingmei
Subjects: Human Genome, Aging, Cancer, Clinical Research, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Age Factors, Asian People, Autophagy-Related Proteins, Body Mass Index, Breast Neoplasms, Chromosome Mapping, Chromosomes, Human, Pair 10, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Luciferases, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regression Analysis, Trans-Activators, Transcription Factors, White People, German Consortium of Hereditary Breast and Ovarian Cancer, kConFab/AOCS Investigators, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
Published: 2015

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

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

40. Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author: Carvajal-Carmona, Luis G, O’Mara, Tracy A, Painter, Jodie N, Lose, Felicity A, Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P, Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S, Pooley, Karen, Beesley, Jonathan, Cheng, Timothy, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, National Study of Endometrial Cancer Genetics Group (NSECG), The Australian National Endometrial Cancer Study Group (ANECS), Wentzensen, Nicholas, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Renner, Stefan P, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C, Goode, Ellen L, Teoman, Attila, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Scott, Rodney J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Wersäll, Ofra, Mints, Miriam, Tham, Emma, RENDOCAS, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L, Southey, Melissa C, Australian Ovarian Cancer Study (AOCS), Ekici, Arif B, Ruebner, Matthias, Johnson, Nichola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K, Meindl, Alfons, Brauch, Hiltrud, The GENICA Network, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Bruinsma, Fiona, Cunningham, Julie M, Fridley, Brooke L, Børresen-Dale, Anne-Lise, Kristensen, Vessela N, Cox, Angela, Swerdlow, Anthony J, Orr, Nicholas, Bolla, Manjeet K, Wang, Qin, Weber, Rachel Palmieri, Chen, Zhihua, Shah, Mitul, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, and Thompson, Deborah J
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Genetic Testing, Human Genome, Prevention, Cancer, Uterine Cancer, 2.1 Biological and endogenous factors, Aetiology, Chromosomes, Human, Pair 5, Databases, Nucleic Acid, Female, Gene Expression Regulation, Neoplastic, Genetic Loci, Haplotypes, Humans, Membrane Proteins, Models, Genetic, Neoplasm Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Telomerase, National Study of Endometrial Cancer Genetics Group, Australian National Endometrial Cancer Study Group, RENDOCAS, Australian Ovarian Cancer Study, GENICA Network, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
Published: 2015

41. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Author: Kuchenbaecker, Karoline B, Ramus, Susan J, Tyrer, Jonathan, Lee, Andrew, Shen, Howard C, Beesley, Jonathan, Lawrenson, Kate, McGuffog, Lesley, Healey, Sue, Lee, Janet M, Spindler, Tassja J, Lin, Yvonne G, Pejovic, Tanja, Bean, Yukie, Li, Qiyuan, Coetzee, Simon, Hazelett, Dennis, Miron, Alexander, Southey, Melissa, Terry, Mary Beth, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Neuhausen, Susan L, Ding, Yuan Chun, Hansen, Thomas VO, Jønson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, Barrowdale, Daniel, Dennis, Joe, Benitez, Javier, Osorio, Ana, Garcia, Maria Jose, Komenaka, Ian, Weitzel, Jeffrey N, Ganschow, Pamela, Peterlongo, Paolo, Bernard, Loris, Viel, Alessandra, Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Radice, Paolo, Papi, Laura, Ottini, Laura, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Frost, Debra, Perkins, Jo, Platte, Radka, Ellis, Steve, EMBRACE, Godwin, Andrew K, Schmutzler, Rita Katharina, Meindl, Alfons, Engel, Christoph, Sutter, Christian, Sinilnikova, Olga M, GEMO Study Collaborators, Damiola, Francesca, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Claes, Kathleen, De Leeneer, Kim, Kirk, Judy, Rodriguez, Gustavo C, Piedmonte, Marion, O'Malley, David M, de la Hoya, Miguel, Caldes, Trinidad, Aittomäki, Kristiina, Nevanlinna, Heli, Collée, J Margriet, Rookus, Matti A, Oosterwijk, Jan C, Breast Cancer Family Registry, Tihomirova, Laima, Tung, Nadine, Hamann, Ute, Isaccs, Claudine, Tischkowitz, Marc, Imyanitov, Evgeny N, Caligo, Maria A, Campbell, Ian G, Hogervorst, Frans BL, HEBON, Olah, Edith, Diez, Orland, Blanco, Ignacio, Brunet, Joan, Lazaro, Conxi, Pujana, Miquel Angel, Jakubowska, Anna, Gronwald, Jacek, Lubinski, Jan, and Sukiennicki, Grzegorz
Subjects: EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, KConFab Investigators, Australian Cancer Study, Australian Ovarian Cancer Study Group, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Quantitative Trait Loci, Adolescent, Adult, Female, Genome-Wide Association Study, Young Adult, Carcinoma, Ovarian Epithelial, Human Genome, Rare Diseases, Genetics, Cancer, Prevention, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Published: 2015

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

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

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

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

44. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

Author: Kelemen, Linda E, Terry, Kathryn L, Goodman, Marc T, Webb, Penelope M, Bandera, Elisa V, McGuire, Valerie, Rossing, Mary Anne, Wang, Qinggang, Dicks, Ed, Tyrer, Jonathan P, Song, Honglin, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Timorek, Agnieszka, Menon, Usha, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Narod, Steven A, Risch, Harvey A, McLaughlin, John R, Siddiqui, Nadeem, Glasspool, Rosalind, Paul, James, Carty, Karen, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Kiemeney, Lambertus A, Massuger, Leon FAG, van Altena, Anne M, Aben, Katja KH, Olson, Sara H, Orlow, Irene, Cramer, Daniel W, Levine, Douglas A, Bisogna, Maria, Giles, Graham G, Southey, Melissa C, Bruinsma, Fiona, Kjaer, Susanne K, Høgdall, Estrid, Jensen, Allan, Høgdall, Claus K, Lundvall, Lene, Engelholm, Svend-Aage, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Thompson, Pamela J, Lurie, Galina, Wilkens, Lynne R, Lambrechts, Diether, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Beesley, Jonathan, AOCS Study Group/ACS Investigators, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Doherty, Jennifer A, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel, Chang-Claude, Jenny, Rudolph, Anja, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Bogdanova, Natalia, Antonenkova, Natalia, Odunsi, Kunle, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Ness, Roberta B, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Wu, Xifeng, Lu, Karen, Liang, Dong, Hildebrandt, Michelle AT, Weber, Rachel Palmieri, and Iversen, Edwin S
Subjects: AOCS Study Group/ACS Investigators, Humans, Carcinoma, Ovarian Neoplasms, Folic Acid Deficiency, Genetic Predisposition to Disease, Folic Acid, Dihydrouracil Dehydrogenase (NADP), Neoplasm Proteins, Diet, Multivariate Analysis, Risk Factors, Case-Control Studies, Energy Intake, Polymorphism, Single Nucleotide, Dietary Supplements, European Continental Ancestry Group, Female, Genome-Wide Association Study, Global Health, Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1, Rare Diseases, Cancer, Ovarian Cancer, Genetics, Nutrition, 2.1 Biological and endogenous factors, Nutrition & Dietetics, Food Science, Food Sciences, Nutrition and Dietetics, Public Health and Health Services
Abstract: ScopeWe reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
Published: 2014

45. Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

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, Bodek, Simon, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, 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, 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, Harraka, Philip, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lee, Jason, Li, Shuai, Lindeman, Geoff, Lippey, Jocelyn, Lipton, Lara, Lobb, Liz, Loi, Sherene, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, 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, Ragunathan, Abi, Robinson, Bridget, Saleh, Mona, Skandarajah, Anita, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Savas, Peter, Scott, Rodney, Scott, Clare, Sexton, Adrienne, Shaw, Joanne, Shelling, Andrew, Srinivasa, Shweta, Simpson, Peter, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, Young, Mary Ann, Zaheed, Milita, Davidson, Aimee L., Michailidou, Kyriaki, Parsons, Michael T., Fortuno, Cristina, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Naven, Marc, Abubakar, Mustapha, Ahearn, Thomas U., Alonso, M. Rosario, Andrulis, Irene L., Antoniou, Antonis C., Auvinen, Päivi, Behrens, Sabine, Bermisheva, Marina A., Bogdanova, Natalia V., Bojesen, Stig E., Brüning, Thomas, Byers, Helen J., Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Collée, J. Margriet, Czene, Kamila, Dörk, Thilo, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, Glendon, Gord, González-Neira, Anna, Grassmann, Felix, Gronwald, Jacek, Guénel, Pascal, Hadjisavvas, Andreas, Haeberle, Lothar, Hall, Per, Hamann, Ute, Hartman, Mikael, Ho, Peh Joo, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Khusnutdinova, Elza K., Kristensen, Vessela N., Li, Jingmei, Lim, Joanna, Lindblom, Annika, Liu, Jenny, Lophatananon, Artitaya, Mannermaa, Arto, Mavroudis, Dimitrios A., Mensenkamp, Arjen R., Milne, Roger L., Muir, Kenneth R., Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Park, Sue K., Park-Simon, Tjoung-Won, Peterlongo, Paolo, Radice, Paolo, Rashid, Muhammad U., Rhenius, Valerie, Saloustros, Emmanouil, Sawyer, Elinor J., Schmidt, Marjanka K., Seibold, Petra, Shah, Mitul, Southey, Melissa C., Teo, Soo Hwang, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, van de Beek, Irma, van der Hout, Annemieke H., Wendt, Camilla C., Dunning, Alison M., Pharoah, Paul D.P., Devilee, Peter, Easton, Douglas F., James, Paul A., and Spurdle, Amanda B.
Published: 2024
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46. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

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

47. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

Author: Hedditch, Ellen L, Gao, Bo, Russell, Amanda J, Lu, Yi, Emmanuel, Catherine, Beesley, Jonathan, Johnatty, Sharon E, Chen, Xiaoqing, Harnett, Paul, George, Joshy, Australian Ovarian Cancer Study Group, Williams, Rebekka T, Flemming, Claudia, Lambrechts, Diether, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Nakanishi, Toru, Yatabe, Yasushi, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susan K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen, Iversen, Ed, Weber, Rachel P, Berchuck, Andrew, Goode, Ellen, Bowtell, David D, Chenevix-Trench, Georgia, deFazio, Anna, Norris, Murray D, MacGregor, Stuart, Haber, Michelle, and Henderson, Michelle J
Subjects: Australian Ovarian Cancer Study Group, Humans, Neoplasms, Glandular and Epithelial, Cystadenocarcinoma, Serous, Ovarian Neoplasms, ATP-Binding Cassette Transporters, RNA, Messenger, Cell Movement, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Female, Neoplastic Stem Cells, Genome-Wide Association Study, Kaplan-Meier Estimate, Real-Time Polymerase Chain Reaction, Neoplasm Grading, ATP Binding Cassette Transporter 1, Carcinoma, Ovarian Epithelial, Ovarian Cancer, Rare Diseases, Biotechnology, Genetics, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
Published: 2014

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

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

49. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Author: Johnatty, Sharon E, Beesley, Jonathan, Gao, Bo, Chen, Xiaoqing, Lu, Yi, Law, Matthew H, Henderson, Michelle J, Russell, Amanda J, Hedditch, Ellen L, Emmanuel, Catherine, Fereday, Sian, Webb, Penelope M, Group, Australian Ovarian Cancer Study, Goode, Ellen L, Vierkant, Robert A, Fridley, Brooke L, Cunningham, Julie M, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Brown, Robert, Paul, Jim, Lambrechts, Sandrina, Despierre, Evelyn, Vergote, Ignace, Lester, Jenny, Karlan, Beth Y, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Bean, Yukie, Pejovic, Tanja, Levine, Douglas A, Goodman, Marc T, Camey, Michael E, Thompson, Pamela J, Lurie, Galina, Shildkraut, Joellen, Berchuck, Andrew, Terry, Kathryn L, Cramer, Daniel W, Norris, Murray D, Haber, Michelle, MacGregor, Stuart, deFazio, Anna, and Chenevix-Trench, Georgia
Subjects: Genetics, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Ovarian Epithelial, Disease Progression, Disease-Free Survival, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Paclitaxel, Pharmacogenetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Ovarian cancer, Polymorphisms, Outcome, Chemotherapy, ABCB1, Australian Ovarian Cancer Study Group, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract: ObjectiveABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).MethodsThe best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.ResultFine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.ConclusionOur study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
Published: 2013

50. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author: Bojesen, Stig E, Pooley, Karen A, Johnatty, Sharon E, Beesley, Jonathan, Michailidou, Kyriaki, Tyrer, Jonathan P, Edwards, Stacey L, Pickett, Hilda A, Shen, Howard C, Smart, Chanel E, Hillman, Kristine M, Mai, Phuong L, Lawrenson, Kate, Stutz, Michael D, Lu, Yi, Karevan, Rod, Woods, Nicholas, Johnston, Rebecca L, French, Juliet D, Chen, Xiaoqing, Weischer, Maren, Nielsen, Sune F, Maranian, Melanie J, Ghoussaini, Maya, Ahmed, Shahana, Baynes, Caroline, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, Healey, Sue, Lush, Michael, Tessier, Daniel C, Vincent, Daniel, Bacot, Françis, Australian Cancer Study, Australian Ovarian Cancer Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Gene Environment Interaction and Breast Cancer (GENICA), Swedish Breast Cancer Study (SWE-BRCA), Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Epidemiological study of BRCA1 & BRCA2 Mutation Carriers (EMBRACE), Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO), Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Risch, Harvey A, González-Neira, Anna, Rossing, Mary Anne, Pita, Guillermo, Doherty, Jennifer A, Alvarez, Nuria, Larson, Melissa C, Fridley, Brooke L, Schoof, Nils, Chang-Claude, Jenny, Cicek, Mine S, Peto, Julian, Kalli, Kimberly R, Broeks, Annegien, Armasu, Sebastian M, Schmidt, Marjanka K, Braaf, Linde M, Winterhoff, Boris, Nevanlinna, Heli, Konecny, Gottfried E, Lambrechts, Diether, Rogmann, Lisa, Guénel, Pascal, Teoman, Attila, Milne, Roger L, Garcia, Joaquin J, Cox, Angela, Shridhar, Vijayalakshmi, Burwinkel, Barbara, Marme, Frederik, Hein, Rebecca, Sawyer, Elinor J, Haiman, Christopher A, Wang-Gohrke, Shan, Andrulis, Irene L, Moysich, Kirsten B, Hopper, John L, Odunsi, Kunle, Lindblom, Annika, Giles, Graham G, Brenner, Hermann, Simard, Jacques, Lurie, Galina, Fasching, Peter A, Carney, Michael E, Radice, Paolo, Wilkens, Lynne R, Swerdlow, Anthony, Goodman, Marc T, Brauch, Hiltrud, Garcia-Closas, Montserrat, and Hillemanns, Peter
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Gene Environment Interaction and Breast Cancer, Swedish Breast Cancer Study, Hereditary Breast and Ovarian Cancer Research Group Netherlands, Epidemiological study of BRCA1 & BRCA2 Mutation Carriers, Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers, Chromatin, Telomere, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, Luciferases, Telomerase, RNA, Messenger, Oligonucleotide Array Sequence Analysis, Risk Factors, Case-Control Studies, Gene Expression Profiling, Reverse Transcriptase Polymerase Chain Reaction, DNA Methylation, Alternative Splicing, Genotype, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Genetic Loci, Real-Time Polymerase Chain Reaction, Biomarkers, Tumor, Genetics, Breast Cancer, Cancer, Ovarian Cancer, Rare Diseases, Prevention, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Published: 2013

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