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1. Objective responses to first-line neoadjuvant carboplatin–paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial

Author

Morgan, Robert D, McNeish, Iain A, Cook, Adrian D, James, Elizabeth C, Lord, Rosemary, Dark, Graham, Glasspool, Rosalind M, Krell, Jonathan, Parkinson, Christine, Poole, Christopher J, Hall, Marcia, Gallardo-Rincón, Dolores, Lockley, Michelle, Essapen, Sharadah, Summers, Jeff, Anand, Anjana, Zachariah, Abel, Williams, Sarah, Jones, Rachel, Scatchard, Kate, Walther, Axel, Kim, Jae-Weon, Sundar, Sudha, Jayson, Gordon C, Ledermann, Jonathan A, and Clamp, Andrew R

Published
2021
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2. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, consortium, The CVD50, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, Hoed, Marcel den, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, and Trompet, Stella

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Research, Diabetes, Human Genome, Cardiovascular, Prevention, Obesity, Genetics, Heart Disease, Heart Disease - Coronary Heart Disease, Clinical Trials and Supportive Activities, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Alleles, Coronary Disease, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Genotype, Glucagon-Like Peptide-1 Receptor, Humans, Receptor, Cannabinoid, CB2, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Sodium-Glucose Transporter 1, CVD50 consortium, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Aging Research in Genomic Epidemiology, Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease, EPIC-InterAct, CHARGE consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016

3. Electronic and transport properties of graphene nanostructures

Author

Poole, Christopher J.

Subjects
620.5
Abstract

Graphene --- a crystal of carbon atoms in a two-dimensional (2D) honeycomb lattice --- is a gapless semiconductor, and has attracted great interest since it was fabricated in 2004 [1-3]. This monolayer of graphite has been shown to have remarkable properties, such as a linear energy dispersion relation [4] and massless, chiral fermions [5]. This thesis discusses some of these properties, as well as those found in bilayer graphene [6- 8]. Bilayer graphene is the formation of two coupled layers of graphene, exhibiting Bernal stacking (to be discussed later), and features massive chiral fermions [9]. Chapter 1 discusses the tight binding model, and derives the Hamiltonians for monolayer and bilayer graphene, used in subsequent Chapters. We also review important phenomena that account for the results seen in later Chapters. In addition to the material discussed in this Chapter, several excellent review articles have been written that cover other features and phenomena in few-layer graphene systems [10-17]. Chapter 2 is original published work. We extend the low energy effective two-band Hamiltonian for electrons in bilayer graphene (McCann and Fal'ko [7]) to include a spatially dependent electrostatic potential. We find that this Hamiltonian contains additional terms, as compared to the one used earlier in the analysis of electronic transport in n-p junctions in bilayers (Katsnelson et al. [9]). However, for potential steps |it| < 7 i (where 71 is the interlayer coupling), corrections to the transmission probability due to such terms are small. For the angle-dependent transmission T(0) we find T(6) = sin2(2$) --- (2u/3/ji) sin(4$) sin($) which slightly increases the Fano factor: F = 0.241 for u = 40meV. Chapter 3 is original work which was carried out simultaneously with Barbier et al. [18]. Nevertheless, the method of analysis and parameters considered are different, and the results are reached independently. Agreement is found with [19-21]. The work focuses on the introduction of a periodic potential profile in monolayer and bilayer graphene systems, creating extra Dirac points in the energy dispersion for monolayer graphene. Classical catastrophe theory is then employed to describe caustics and cusps in a system with a periodic potential profile, for cusps forming at regular interfaces. The periodicity of the formation of cusps is matched with the periodicity of the superlattice. The energy at which this occurs is then mapped to the energy spectrum found when analysing monolayer graphene with a periodic potential profile. In Chapter 4 we create a model to characterise the angles and commensurability of a few layers of hexagonal lattice materials, seen in STM images in experiments. The model allows for different lattice constants and rotations for each layer, as well as selectively showing lattice sites that are nearly commensurate with sites in other layers. Two popular cases are turbostratic graphene (bilayer graphene where one layer is rotated relative to the other) and graphene on hBN (hexagonal boron nitride). Finally, appendices with complete source code to reproduce these results are given, with examples of their usage.

Published
2012

4. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial

Author

Earl, Helena M, Hiller, Louise, Howard, Helen C, Dunn, Janet A, Young, Jennie, Bowden, Sarah J, McDermaid, Michelle, Waterhouse, Anna K, Wilson, Gregory, Agrawal, Rajiv, O'Reilly, Susan, Bowman, Angela, Ritchie, Diana M, Goodman, Andrew, Hickish, Tamas, McAdam, Karen, Cameron, David, Dodwell, David, Rea, Daniel W, Caldas, Carlos, Provenzano, Elena, Abraham, Jean E, Canney, Peter, Crown, John P, Kennedy, M John, Coleman, Robert, Leonard, Robert C, Carmichael, James A, Wardley, Andrew M, and Poole, Christopher J

Published
2017
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5. Supplementary Tables 1 - 5, Figures 1 - 2 from Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

Author

Abraham, Jean E., primary, Guo, Qi, primary, Dorling, Leila, primary, Tyrer, Jonathan, primary, Ingle, Susan, primary, Hardy, Richard, primary, Vallier, Anne-Laure, primary, Hiller, Louise, primary, Burns, Russell, primary, Jones, Linda, primary, Bowden, Sarah J., primary, Dunn, Janet A., primary, Poole, Christopher J., primary, Caldas, Carlos, primary, Pharoah, Paul P.D., primary, and Earl, Helena M., primary

Published
2023
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6. Abstract OT3-32-01: OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Author

Stein, Robert, primary, Makris, Andreas, additional, Macpherson, Iain, additional, Hughes-Davies, Luke, additional, Marshall, Andrea, additional, Dotchin, Georgina, additional, Cameron, David A., additional, Kiely, Belinda E., additional, Wilson, Caroline, additional, Armstrong, Anne, additional, Earl, Helena M., additional, Poole, Christopher J., additional, Tsang, Janice, additional, Naume, Bjørn, additional, Rea, Daniel, additional, Ohnstad, Hege, additional, Hall, Peter S., additional, McIntosh, Stuart A., additional, Shinkins, Bethany, additional, McCabe, Christopher, additional, Morgan, Adrienne, additional, Bartlett, John MS, additional, and Dunn, Janet A., additional

Published
2023
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7. Body mass index and breast cancer survival: a Mendelian randomization analysis

Author

Guo, Qi, Burgess, Stephen, Turman, Constance, Bolla, Manjeet K, Wang, Qin, Lush, Michael, Abraham, Jean, Aittomäki, Kristiina, Andrulis, Irene L, Apicella, Carmel, Arndt, Volker, Barrdahl, Myrto, Benitez, Javier, Berg, Christine D, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Brand, Judith S, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldas, Carlos, Campa, Daniele, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Diver, Ryan W, Dunning, Alison M, Earl, Helena M, Eccles, Diana M, Ekici, Arif B, Eriksson, Mikael, Evans, Gareth D, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Grip, Mervi, Gronwald, Jacek, Haeberle, Lothar, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hankinson, Susan, Hartikainen, Jaana M, Hein, Alexander, Hiller, Louise, Hogervorst, Frans B, Holleczek, Bernd, Hooning, Maartje J, Hoover, Robert N, Humphreys, Keith, Hunter, David J, Hüsing, Anika, Jakubowska, Anna, Jukkola-Vuorinen, Arja, Kaaks, Rudolf, Kabisch, Maria, Kataja, Vesa, Knight, Julia A, Koppert, Linetta B, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindström, Sara, Lissowska, Jolanta, Lubinski, Jan, Machiela, Mitchell J, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Federik, Martens, John WM, McLean, Catriona, Menéndez, Primitiva, Milne, Roger L, Marie Mulligan, Anna, Muranen, Taru A, Nevanlinna, Heli, Neven, Patrick, Nielsen, Sune F, Nordestgaard, Børge G, Olson, Janet E, Perez, Jose IA, Peterlongo, Paolo, Phillips, Kelly-Anne, Poole, Christopher J, Pylkäs, Katri, Radice, Paolo, Rahman, Nazneen, Rüdiger, Thomas, Rudolph, Anja, Sawyer, Elinor J, Schumacher, Fredrick, Seibold, Petra, Seynaeve, Caroline, Shah, Mitul, Smeets, Ann, Southey, Melissa C, Tollenaar, Rob A E M, Tomlinson, Ian, Tsimiklis, Helen, Ulmer, Hans-Ulrich, Vachon, Celine, van den Ouweland, Ans MW, Vanʼt Veer, Laura J, Wildiers, Hans, Willett, Walter, Winqvist, Robert, Zamora, Pilar M, Chenevix-Trench, Georgia, Dörk, Thilo, Easton, Douglas F, García-Closas, Montserrat, Kraft, Peter, Hopper, John L, Zheng, Wei, Schmidt, Marjanka K, and Pharoah, Paul DP

Published
2017
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10. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer

Author

Poole, Christopher J., Earl, Helena M.; Hiller, Louise, Dunn, Janet A.; Bathers, Sarah; Grieve, Robert J.; Spooner, David A., Agrawal, Rajiv K.; Fernando, Indrajit N., Brunt, Murray A.; O'Reilly, Susan M., Crawford, Michael S.; Rea, Daniel W., Simmonds, Peter; Mansi, Janine L.; Stanley, Andrew; Harvey, Peter, McAdam, Karen; Foster, Liz, and Leonard, Robert C.F.; Twelves, Christopher J.

Subjects
Breast cancer -- Drug therapy, Epirubicin -- Dosage and administration, Cyclophosphamide -- Dosage and administration, Methotrexate -- Dosage and administration, Fluorouracil -- Dosage and administration, Cancer -- Adjuvant treatment, Cancer -- Health aspects
Abstract

The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial were designed jointly by English and Scottish investigators in 1994 and 1995 to determine the value of anthracyclines in the adjuvant treatment of early breast cancer. Adjuvant treatment of early breast cancer with epirubicin plus CMF was significantly superior over CMF alone in terms of relapse free survival and overall survival, and hence epirubicin plus CMF as an option for anthracycline-based adjuvant chemotherapy in women with early breast cancer was recommended.

Published
2006

15. Abstract OT3-17-01: OPTIMA: A prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in mostly node-positive early breast cancer

Author

Stein, Robert C, primary, Marshall, Andrea, additional, Makris, Andreas, additional, Hughes-Davies, Luke, additional, MacPherson, Iain R, additional, Conefrey, Carmel, additional, Rooshenas, Leila, additional, Pinder, Sarah E, additional, Shaaban, Abeer M, additional, Naume, Bjørn, additional, Cameron, David A, additional, Rea, Daniel W, additional, Earl, Helena M, additional, Poole, Christopher J, additional, Hall, Peter S, additional, Dotchin, Georgina, additional, McIntosh, Stuart A, additional, Harmer, Victoria, additional, Morgan, Adrienne, additional, Shinkins, Bethany, additional, Stallard, Nigel, additional, McCabe, Christopher, additional, Donovan, Jenny L, additional, Bartlett, John MS, additional, and Dunn, Janet A, additional

Published
2020
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16. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial

Author

Fernando, Indrajit N., primary, Bowden, Sarah J., additional, Herring, Kathryn, additional, Brookes, Cassandra L., additional, Ahmed, Ikhlaaq, additional, Marshall, Andrea, additional, Grieve, Robert, additional, Churn, Mark, additional, Spooner, David, additional, Latief, Talaat N., additional, Agrawal, Rajiv K., additional, Brunt, Adrian M., additional, Stevens, Andrea, additional, Goodman, Andrew, additional, Canney, Peter, additional, Bishop, Jill, additional, Ritchie, Diana, additional, Dunn, Janet, additional, Poole, Christopher J., additional, and Rea, Daniel W., additional

Published
2020
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19. OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer

Author

Stein, Robert C, Makris, Andreas, Hughes-Davies, Luke, Macpherson, Iain R, Hall, Peter S, Cameron, David A, Earl, Helena M, Pinder, Sarah E, Poole, Christopher J, Rea, Daniel W, McIntosh, Stuart, Harmer, Victoria, Morgan, Adrienne, Rooshenas, Leila, Conefrey, Carmel, Donovan, Jenny L, Hulme, Claire, McCabe, Christopher, Stallard, Nigel, Campbell, Amy, Higgins, Helen, Bartlett, John MS, Marshall, Andrea, and Dunn, Janet A

Subjects
skin and connective tissue diseases
Abstract

Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk in hormone-sensitive HER2-negative node-negative early breast cancer, allowing patients with low risk to safely avoid chemotherapy. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) aims to validate MPA’s as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population.

Published
2018
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20. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with Venous Thromboembolism: Results of a randomized trial (SELECT-D)

Author

Young, Annie M., Marshall, Andrea, Thirlwall, Jenny, Chapman, Oliver, Lokare, Anand, Hill, Catherine, Hale, Danielle, Dunn, Janet A., Lyman, Gary H., Hutchinson, Charles, MacCallum, Peter, Kakkar, Ajay, Hobbs, F. D. Richard, Petrou, Stavros, Dale, Jeremy, Poole, Christopher J., Maraveyas, Anthony, Levine, Mark, and HASH(0x5651c9dbb470)

Subjects
Cancer Research, medicine.medical_specialty, medicine.drug_mechanism_of_action, medicine.drug_class, Deep vein, Factor Xa Inhibitor, Low molecular weight heparin, 030204 cardiovascular system & hematology, law.invention, RC0254, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Rivaroxaban, business.industry, Standard treatment, medicine.disease, Pulmonary embolism, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, business, Fibrinolytic agent, medicine.drug
Abstract

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Published
2018

21. Body mass index and breast cancer survival:a Mendelian randomization analysis

Author

Guo, Qi, Burgess, Stephen, Turman, Constance, Bolla, Manjeet K, Wang, Qin, Lush, Michael, Abraham, Jean, Aittomäki, Kristiina, Andrulis, Irene L, Apicella, Carmel, Arndt, Volker, Barrdahl, Myrto, Benitez, Javier, Berg, Christine D, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Brand, Judith S, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldas, Carlos, Campa, Daniele, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Diver, W Ryan, Dunning, Alison M, Earl, Helena M, Eccles, Diana M, Ekici, Arif B, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Grip, Mervi, Gronwald, Jacek, Haeberle, Lothar, Hall, Per, Hamann, Ute, Hankinson, Susan, Hartikainen, Jaana M, Hein, Alexander, Hiller, Louise, Hogervorst, Frans B, Holleczek, Bernd, Hooning, Maartje J, Hoover, Robert N, Humphreys, Keith, Hunter, David J, Hüsing, Anika, Jakubowska, Anna, Jukkola-Vuorinen, Arja, Kaaks, Rudolf, Kabisch, Maria, Kataja, Vesa, Knight, Julia A, Koppert, Linetta B, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindblom, Annika, Lindström, Sara, Lissowska, Jolanta, Lubinski, Jan, Machiela, Mitchell J, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Federik, Martens, John WM, McLean, Catriona, Menéndez, Primitiva, Milne, Roger L, Mulligan, Anna Marie, Muranen, Taru A, Nevanlinna, Heli, Neven, Patrick, Nielsen, Sune F, Nordestgaard, Børge G, Olson, Janet E, Perez, Jose IA, Peterlongo, Paolo, Phillips, Kelly-Anne, Poole, Christopher J, Pylkäs, Katri, Radice, Paolo, Rahman, Nazneen, Rüdiger, Thomas, Rudolph, Anja, Sawyer, Elinor J, Schumacher, Fredrick, Seibold, Petra, Seynaeve, Caroline, Shah, Mitul, Smeets, Ann, Southey, Melissa C, Tollenaar, Rob A E M, Tomlinson, Ian, Tsimiklis, Helen, Ulmer, Hans Ulrich, Vachon, Celine, van den Ouweland, Ans MW, Van't Veer, Laura J, Wildiers, Hans, Willett, Walter, Winqvist, Robert, Pilar Zamora, M, Chenevix-Trench, Georgia, Dörk, Thilo, Easton, Douglas F., García-Closas, Montserrat, Kraft, Peter, Hopper, John L, Zheng, Wei, Schmidt, Marjanka K, and Pharoah, Paul DP

Abstract

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Published
2017
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22. The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

Author

Dorling, L, Kar, Siddhartha, Michailidou, Kyriaki, Hiller, Louise, Vallier, Anne-Laure, Ingle, Susan, Hardy, Richard, Bowden, Sarah J., Dunn, Janet A., Twelves, Chris, Poole, Christopher J., Caldas, Carlos, Earl, Helena M., Pharoah, Paul D. P., Abraham, Jean E., Dorling, Leila [0000-0003-1214-8080], and Apollo - University of Cambridge Repository

Subjects
Cancer Treatment, lcsh:Medicine, Toxicology, Pathology and Laboratory Medicine, White Blood Cells, Risk Factors, Animal Cells, Antineoplastic Combined Chemotherapy Protocols, Breast Tumors, Medicine and Health Sciences, lcsh:Science, Pharmaceutics, Genomics, Middle Aged, Survival Rate, Oncology, Neurology, Female, Cellular Types, Research Article, Adult, Clinical Oncology, Neutropenia, Immune Cells, Immunology, Breast Neoplasms, Polymorphism, Single Nucleotide, Disease-Free Survival, RC0254, Drug Therapy, Breast Cancer, Biomarkers, Tumor, Genetics, Genome-Wide Association Studies, Humans, Chemotherapy, Aged, Blood Cells, Toxicity, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Genome Analysis, Pharmacogenomic Testing, Neuropathy, lcsh:Q, Clinical Medicine
Abstract

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.\ud \ud

Published
2016

23. Common germline polymorphisms associated with breast cancer-specific survival

Author

Pirie, Ailith, Guo, Qi, Kraft, Peter, Canisius, Sander, Eccles, Diana M, Rahman, Nazneen, Nevanlinna, Heli, Chen, Constance, Khan, Sofia, Tyrer, Jonathan, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Dunning, Alison M, Shah, Mitul, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Lambrechts, Dieter, Weltens, Caroline, Leunen, Karin, van Ongeval, Chantal, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Blomqvist, Carl, Aittomäki, Kristiina, Fagerholm, Rainer, Muranen, Taru A, Olsen, Janet E, Hallberg, Emily, Vachon, Celine, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Broeks, Annegien, Cornelissen, Sten, Haiman, Christopher A, Henderson, Brian E, Schumacher, Frederick, Le Marchand, Loic, Hopper, John L, Tsimiklis, Helen, Apicella, Carmel, Southey, Melissa C, Cross, Simon S, Reed, Malcolm Wr, Giles, Graham G, Milne, Roger L, McLean, Catriona, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Hooning, Maartje J, Hollestelle, Antoinette, Martens, John Wm, van den Ouweland, Ans Mw, Marme, Federick, Schneeweiss, Andreas, Yang, Rongxi, Burwinkel, Barbara, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Brenner, Hermann, Butterbach, Katja, Holleczek, Bernd, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Devilee, Peter, Tollenaar, Robert Aem, Seynaeve, Caroline, Radice, Paolo, Peterlongo, Paolo, Manoukian, Siranoush, Ficarazzi, Filomena, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Balleine, Rosemary, Phillips, Kelly-Anne, kConFab Investigators, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Jakubowska, Anna, Lubinski, Jan, Gronwald, Jacek, Durda, Katarzyna, Hamann, Ute, Kabisch, Maria, Ulmer, Hans Ulrich, Rüdiger, Thomas, Margolin, Sara, Kristensen, Vessela, Nord, Siljie, NBCS Investigators, Evans, D Gareth, Abraham, Jean, Earl, Helena, Poole, Christopher J, Hiller, Louise, Dunn, Janet A, Bowden, Sarah, Yang, Rose, Campa, Daniele, Diver, W Ryan, Gapstur, Susan M, Gaudet, Mia M, Hankinson, Susan, Hoover, Robert N, Hüsing, Anika, Kaaks, Rudolf, Machiela, Mitchell J, Willett, Walter, Barrdahl, Myrto, Canzian, Federico, Chin, Suet-Feung, Caldas, Carlos, Hunter, David J, Lindstrom, Sara, Garcia-Closas, Montserrat, Couch, Fergus J, Chenevix-Trench, Georgia, Mannermaa, Arto, Andrulis, Irene L, Hall, Per, Chang-Claude, Jenny, Easton, Douglas F, Bojesen, Stig E, Cox, Angela, Fasching, Peter A, Pharoah, Paul Dp, Schmidt, Marjanka K, Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Abraham, Jean [0000-0003-0688-4807], Earl, Helena [0000-0003-1549-8094], Chin, Suet-Feung [0000-0001-5697-1082], Caldas, Carlos [0000-0003-3547-1489], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Obstetrics & Gynecology, Clinical Genetics, and Medical Oncology

Subjects
PROGNOSIS, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENOME-WIDE ASSOCIATION, THAN-T POLYMORPHISM, GENETIC POLYMORPHISMS, ADJUVANT THERAPY, RISK, OUTCOMES, VARIANTS, GENOTYPE, Breast Neoplasms, Polymorphism, Single Nucleotide, RC0254, SDG 3 - Good Health and Well-being, Medizinische Fakultät, Humans, Genetic Predisposition to Disease, ddc:610, skin and connective tissue diseases, Genetic Association Studies, Medicine(all), Prognosis, Germ Cells, Female, Genome-Wide Association Study, Research Article
Abstract

Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value

Published
2015

24. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancakova, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Ines, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jorgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Galle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Mueller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Borge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quiros, J. Ramn, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sanchez, Mara-Jose, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adams., Dupuis, Josee, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jorgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., Waterworth, Dawn M., Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancakova, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Ines, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jorgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Galle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Mueller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Borge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quiros, J. Ramn, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sanchez, Mara-Jose, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adams., Dupuis, Josee, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jorgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., and Waterworth, Dawn M.

Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016
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25. OPTIMA (Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis): A prospective trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions

Author

Francis, Adele, primary, Stein, Robert C., additional, Marshall, Andrea, additional, Rea, Daniel W., additional, Cameron, David A., additional, Macpherson, Iain R., additional, Earl, Helena M., additional, Poole, Christopher J., additional, Hall, Peter S., additional, Bartlett, John M.S., additional, Rooshenas, Leila, additional, Morgan, Adrienne, additional, Harmer, Victoria, additional, Donovan, Jenny, additional, Hulme, Claire, additional, McCabe, Christopher, additional, Pinder, Sarah E., additional, Hughes-Davies, Luke, additional, Makris, Andreas, additional, and Dunn, Janet A., additional

Published
2016
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26. A nested cohort study of 6,248 early breast cancer patients treated in neoadjuvant and adjuvant chemotherapy trials investigating the prognostic value of chemotherapy-related toxicities

Author

Abraham, Jean E., primary, Hiller, Louise, additional, Dorling, Leila, additional, Vallier, Anne-Laure, additional, Dunn, Janet, additional, Bowden, Sarah, additional, Ingle, Susan, additional, Jones, Linda, additional, Hardy, Richard, additional, Twelves, Christopher, additional, Poole, Christopher J., additional, Pharoah, Paul D P, additional, Caldas, Carlos, additional, and Earl, Helena M., additional

Published
2015
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27. Predicting Anthracycline Benefit: TOP2A and CEP17—Not Only but Also

Author

Bartlett, John M.S., primary, McConkey, Christopher C., additional, Munro, Alison F., additional, Desmedt, Christine, additional, Dunn, Janet A., additional, Larsimont, Denis P., additional, O'Malley, Frances P., additional, Cameron, David A., additional, Earl, Helena M., additional, Poole, Christopher J., additional, Shepherd, Lois E., additional, Cardoso, Fatima, additional, Jensen, Maj-Britt, additional, Caldas, Carlos, additional, Twelves, Christopher J., additional, Rea, Daniel W., additional, Ejlertsen, Bent, additional, Di Leo, Angelo, additional, and Pritchard, Kathleen I., additional

Published
2015
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28. Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

Author

Abraham, Jean E., primary, Guo, Qi, additional, Dorling, Leila, additional, Tyrer, Jonathan, additional, Ingle, Susan, additional, Hardy, Richard, additional, Vallier, Anne-Laure, additional, Hiller, Louise, additional, Burns, Russell, additional, Jones, Linda, additional, Bowden, Sarah J., additional, Dunn, Janet A., additional, Poole, Christopher J., additional, Caldas, Carlos, additional, Pharoah, Paul P.D., additional, and Earl, Helena M., additional

Published
2014
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29. Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others.

Author

Bartlett, John M. S., Bayani, Jane, Marshall, Andrea, Dunn, Janet A., Campbell, Amy, Cunningham, Carrie, Sobol, Monika S., Hall, Peter S., Poole, Christopher J., Cameron, David A., Earl, Helena M., Rea, Daniel W., Macpherson, Iain R., Canney, Peter, Francis, Adele, McCabe, Christopher, Pinder, Sarah E., Hughes-Davies, Luke, Makris, Andreas, and Stein, Robert C.

Subjects
BREAST cancer diagnosis, HEALTH risk assessment, ROUTINE diagnostic tests, HORMONE receptor positive breast cancer, BREAST cancer patients
Abstract

Background: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population.Methods: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna.Results: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors.Conclusions: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information. [ABSTRACT FROM AUTHOR]

Published
2016
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33. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, Van Der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, CVD50 Consortium, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, Den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, Trompet, Stella, Tumino, Rosario, Van Der A, Daphne L, Van Der Schouw, Yvonne T, Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, GERAD_EC Consortium, Neurology Working Group Of The Cohorts For Heart, Aging Research In Genomic Epidemiology (CHARGE), Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation Into Cancer And Nutrition–Cardiovascular Disease (EPIC-CVD), EPIC-InterAct, Abraham, Jean E, Amundadottir, Laufey T, Aponte, Jennifer L, Butterworth, Adam S, Dupuis, Josée, Easton, Douglas F, Eeles, Rosalind A, Erdmann, Jeanette, Franks, Paul W, Frayling, Timothy M, Hansen, Torben, Howson, Joanna MM, Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I, Pankow, James S, Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I, Saleheen, Danish, Samani, Nilesh J, Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, CHARGE Consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Deloukas, Panos, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, and Waterworth, Dawn M

Subjects
Receptor, Cannabinoid, CB2, Sodium-Glucose Transporter 1, Diabetes Mellitus, Type 2, Genotype, Dipeptidyl Peptidase 4, Receptor, Serotonin, 5-HT2C, Humans, Coronary Disease, Obesity, Receptors, Somatostatin, Alleles, Glucagon-Like Peptide-1 Receptor, 3. Good health
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

34. The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

Author

Dorling, Leila, Kar, Siddhartha, Michailidou, Kyriaki, Hiller, Louise, Vallier, Anne-Laure, Ingle, Susan, Hardy, Richard, Bowden, Sarah J, Dunn, Janet A, Twelves, Chris, Poole, Christopher J, Caldas, Carlos, Earl, Helena M, Pharoah, Paul DP, and Abraham, Jean E

Subjects
Adult, Neutropenia, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Disease-Free Survival, 3. Good health, Pharmacogenomic Testing, Survival Rate, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Female, Aged
Abstract

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.

35. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Michailidou, Kyriaki, Trompet, Stella, Forouhi, Nita G., Garcia, Sara Benlloch, Young, Robin, Kontto, Jukka, Jørgensen, Torben, Kooner, Jaspal, Boeing, Heiner, Dunn, Janet A., Ehm, Margaret G., Waterworth, Dawn M., Boehnke, Michael, Maruthur, Nisa, Eeles, Rosalind A., Luan, Jian'an, Walker, Mark, Kee, Frank, Al Olama, Ali Amin, Earl, Helena M., Pankow, James S., Sattar, Naveed, Thompson, Deborah J., Pedersen, Oluf, Jukema, J. Wouter, Cruchaga, Carlos, Boerwinkle, Eric, Foltynie, Thomas, Poole, Christopher J., Sims, Rebecca, Packard, Chris J., Key, Timothy J., Müller-Nurasyid, Martina, Kraja, Aldi T., Gonzalez, Carlos, Vollenweider, Peter, Danesh, John, Bork-Jensen, Jette, Kuulasmaa, Kari, O'Rahilly, Stephen, Van Der A, Daphne L., Amouyel, Philippe, Balkau, Beverley, Aponte, Jennifer L, Munroe, Patricia B., Ferrieres, Jean, Van Der Schouw, Yvonne T., Cupples, L. Adrienne, Chu, Audrey Y., Butterworth, Adam S., Barroso, Inês, Saleheen, Danish, Salomaa, Veikko, Easton, Douglas F., Hiller, Louise, Arriola, Larraitz, Grarup, Niels, Mohlke, Karen L, Czajkowski, Jacek, Marenne, Gaëlle, Chen, Yuning, Caslake, Muriel, Nielsen, Sune F., Walter, Klaudia, Riboli, Elio, Bis, Joshua C., Jørgensen, Marit E., Ehret, Georg B., Amundadottir, Laufey T., Nilsson, Peter M., Grioni, Sara, Blankenberg, Stefan, Tumino, Rosario, Pirie, Ailith, Slimani, Nadia, Schunkert, Heribert, Caldas, Carlos, Rolandsson, Olov, Borecki, Ingrid B., Navarro, Carmen, Willems, Sara M., Smith, Jennifer A., Den Hoed, Marcel, Barricarte, Aurelio, Van Der Lee, Sven J., Meigs, James B., Jansson, Jan-Håkan, Stancáková, Alena, Franks, Paul W., Wareham, Nicholas J., Deloukas, Panos, Morris, Andrew P., Bowden, Sarah, Liu, Chunyu, Samani, Nilesh J., Kathiresan, Sekar, Palli, Domenico, Li, Li, Quirós, J. Ramón, McCarthy, Mark I., Peloso, Gina M., Kuusisto, Johanna, Panico, Salvatore, Goodarzi, Mark O., Peters, Annette, Rotter, Jerome I., Gianfagna, Francesco, Sharp, Stephen J., Hansen, Torben, Erdmann, Jeanette, Arveiler, Dominique, Virtamo, Jarmo, Kerrison, Nicola D., Freitag, Daniel F., Muir, Kenneth, Zhao, Jing Hua, Nordestgaard, Børge G., Abraham, Jean E., Yaghootkar, Hanieh, Perola, Markus, Dupuis, Josée, Linneberg, Allan, Aviles-Olmos, Iciar, Ferrannini, Ele, Kaaks, Rudolf, Scott, Robert A., Kote-Jarai, Zsofia, Ford, Ian, Frayling, Timothy M., Surendran, Praveen, Varga, Tibor V., Laakso, Markku, Gillson, Christopher, Wessel, Jennifer, Sacerdote, Carlotta, Howson, Joanna M.M., Sánchez, María-José, and Wang, Shuai

Subjects
3. Good health
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

36. Electronic and Transport Properties of Graphene Nanostructures.

Author

Poole, Christopher J and Poole, Christopher J

Abstract

Graphene --- a crystal of carbon atoms in a two-dimensional (2D) honeycomb lattice --- is a gapless semiconductor, and has attracted great interest since it was fabricated in 2004 [1-3]. This monolayer of graphite has been shown to have remarkable properties, such as a linear energy dispersion relation [4] and massless, chiral fermions [5]. This thesis discusses some of these properties, as well as those found in bilayer graphene [6- 8]. Bilayer graphene is the formation of two coupled layers of graphene, exhibiting Bernal stacking (to be discussed later), and features massive chiral fermions [9]. Chapter 1 discusses the tight binding model, and derives the Hamiltonians for monolayer and bilayer graphene, used in subsequent Chapters. We also review important phenomena that account for the results seen in later Chapters. In addition to the material discussed in this Chapter, several excellent review articles have been written that cover other features and phenomena in few-layer graphene systems [10-17]. Chapter 2 is original published work. We extend the low energy effective two-band Hamiltonian for electrons in bilayer graphene (McCann and Fal'ko [7]) to include a spatially dependent electrostatic potential. We find that this Hamiltonian contains additional terms, as compared to the one used earlier in the analysis of electronic transport in n-p junctions in bilayers (Katsnelson et al. [9]). However, for potential steps |it| < 7 i (where 71 is the interlayer coupling), corrections to the transmission probability due to such terms are small. For the angle-dependent transmission T(0) we find T(6) = sin2(2$) --- (2u/3/ji) sin(4$) sin($) which slightly increases the Fano factor: F = 0.241 for u = 40meV. Chapter 3 is original work which was carried out simultaneously with Barbier et al. [18]. Nevertheless, the method of analysis and parameters considered are different, and the results are reached independently. Agreement is found with [19-21]. The work focuses on the int

37. Electronic and Transport Properties of Graphene Nanostructures.

Author

Poole, Christopher J and Poole, Christopher J

Abstract

Graphene --- a crystal of carbon atoms in a two-dimensional (2D) honeycomb lattice --- is a gapless semiconductor, and has attracted great interest since it was fabricated in 2004 [1-3]. This monolayer of graphite has been shown to have remarkable properties, such as a linear energy dispersion relation [4] and massless, chiral fermions [5]. This thesis discusses some of these properties, as well as those found in bilayer graphene [6- 8]. Bilayer graphene is the formation of two coupled layers of graphene, exhibiting Bernal stacking (to be discussed later), and features massive chiral fermions [9]. Chapter 1 discusses the tight binding model, and derives the Hamiltonians for monolayer and bilayer graphene, used in subsequent Chapters. We also review important phenomena that account for the results seen in later Chapters. In addition to the material discussed in this Chapter, several excellent review articles have been written that cover other features and phenomena in few-layer graphene systems [10-17]. Chapter 2 is original published work. We extend the low energy effective two-band Hamiltonian for electrons in bilayer graphene (McCann and Fal'ko [7]) to include a spatially dependent electrostatic potential. We find that this Hamiltonian contains additional terms, as compared to the one used earlier in the analysis of electronic transport in n-p junctions in bilayers (Katsnelson et al. [9]). However, for potential steps |it| < 7 i (where 71 is the interlayer coupling), corrections to the transmission probability due to such terms are small. For the angle-dependent transmission T(0) we find T(6) = sin2(2$) --- (2u/3/ji) sin(4$) sin($) which slightly increases the Fano factor: F = 0.241 for u = 40meV. Chapter 3 is original work which was carried out simultaneously with Barbier et al. [18]. Nevertheless, the method of analysis and parameters considered are different, and the results are reached independently. Agreement is found with [19-21]. The work focuses on the int

38. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1Rvariant protective for coronary heart disease

Author

Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Børge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adam S., Dupuis, Josée, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O’Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., and Waterworth, Dawn M.

Abstract

A missense variant in GLP1R associated with lower fasting glucose levels and protective against T2D is associated with lower risk of coronary heart disease, suggesting that GLP1R agonists are not associated with an unacceptable increase in cardiovascular risk.

Published
2016
Full Text
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39. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Nicola D. Kerrison, Carlos González, Mark Walker, Adam S. Butterworth, Martina Müller-Nurasyid, Mark I. McCarthy, Jarmo Virtamo, Nilesh J. Samani, Daniel F. Freitag, Jennifer Wessel, Inês Barroso, Jette Bork-Jensen, Marit E. Jørgensen, Torben Hansen, Nita G. Forouhi, Jennifer A. Smith, Peter Vollenweider, Douglas F. Easton, Heiner Boeing, Helena M. Earl, Laufey T. Amundadottir, Annette Peters, Ingrid B. Borecki, L. Adrienne Cupples, Li Li, Josée Dupuis, Sara Benlloch Garcia, J. Wouter Jukema, Shuai Wang, Veikko Salomaa, Jukka Kontto, Timothy J. Key, Yuning Chen, Sune F. Nielsen, Robin Young, Jing Hua Zhao, Andrew P. Morris, Larraitz Arriola, Claudia Langenberg, Joshua C. Bis, Nisa M. Maruthur, Ele Ferrannini, Joanna M. M. Howson, Marcel den Hoed, Jeanette Erdmann, Rosalind A. Eeles, Daphne L. van der A, Panos Deloukas, Eric Boerwinkle, Sara M. Willems, Elio Riboli, Markku Laakso, Gina M. Peloso, Muriel J. Caslake, Nadia Slimani, Zsofia Kote-Jarai, Paul W. Franks, EPIC-InterAct, Dominique Arveiler, Sarah Bowden, Janet A. Dunn, Jan-Håkan Jansson, Carlos Cruchaga, Audrey Y. Chu, James S. Pankow, Rudolf Kaaks, Jerome I. Rotter, Jaspal S. Kooner, Ailith Pirie, Johanna Kuusisto, Hanieh Yaghootkar, Niels Grarup, Danish Saleheen, Thomas Foltynie, Jean Abraham, Stefan Blankenberg, Mark O. Goodarzi, Markus Perola, Olov Rolandsson, Chris J. Packard, Praveen Surendran, Allan Linneberg, Beverley Balkau, Christopher J. Poole, Frank Kee, Carmen Navarro, Nicholas J. Wareham, Oluf Pedersen, Heribert Schunkert, Domenico Palli, Patricia B. Munroe, Sven J. van der Lee, Chunyu Liu, Rebecca Sims, Georg Ehret, Michael Boehnke, Stephen J. Sharp, Peter M. Nilsson, Salvatore Panico, Børge G. Nordestgaard, Aldi T. Kraja, Sara Grioni, Sekar Kathiresan, Dawn M. Waterworth, Francesco Gianfagna, Jacek Czajkowski, Naveed Sattar, Margaret G. Ehm, Christopher J. Gillson, Karen L. Mohlke, Stella Trompet, John Danesh, Carlotta Sacerdote, Gaëlle Marenne, Jian'an Luan, Timothy M. Frayling, J. Ramón Quirós, Iciar Aviles-Olmos, Robert A. Scott, Yvonne T. van der Schouw, Jennifer L. Aponte, María José Sánchez, Deborah J. Thompson, Klaudia Walter, James B. Meigs, Tibor V. Varga, Kari Kuulasmaa, Torben Jørgensen, Rosario Tumino, Kyriaki Michailidou, Kenneth Muir, Philippe Amouyel, Ian Ford, Aurelio Barricarte, Stephen O'Rahilly, Ali Amin Al Olama, Louise Hiller, Alena Stančáková, Carlos Caldas, Jean Ferrières, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niel, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'An, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inê, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bowden, Sarah, Caldas, Carlo, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlo, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thoma, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlo, Grioni, Sara, Hiller, Louise, Jansson, Jan Håkan, Jørgensen, Marit E, Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Marku, Peters, Annette, Poole, Christopher J, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, Trompet, Stella, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E, Amundadottir, Laufey T, Aponte, Jennifer L, Butterworth, Adam S, Dupuis, Josée, Easton, Douglas F, Eeles, Rosalind A, Erdmann, Jeanette, Franks, Paul W, Frayling, Timothy M, Hansen, Torben, Howson, Joanna M. M, Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, Mccarthy, Mark I, Pankow, James S, Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I, Saleheen, Danish, Samani, Nilesh J, Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Pano, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, Waterworth, Dawn M., Surgery, Epidemiology, Ehret, Georg Benedikt, Surendran, Praveen [0000-0002-4911-6077], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Caldas, Carlos [0000-0003-3547-1489], Earl, Helena [0000-0003-1549-8094], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Thompson, Deborah [0000-0003-1465-5799], Abraham, Jean [0000-0003-0688-4807], Butterworth, Adam [0000-0002-6915-9015], Easton, Douglas [0000-0003-2444-3247], Howson, Joanna [0000-0001-7618-0050], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Type 2/genetics, 0301 basic medicine, Somatostatin/genetics, Heart disease, Epidemiology, CHARGE consortium, Obesity/genetics, RECEPTOR AGONIST LIXISENATIDE, Coronary Disease, Type 2 diabetes, Research & Experimental Medicine, Bioinformatics, PLACEBO-CONTROLLED TRIAL, Receptor, Cannabinoid, CB2, DOUBLE-BLIND, Dipeptidyl Peptidase 4/genetics, 0302 clinical medicine, ONCE-DAILY LIXISENATIDE, Receptors, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Exome sequencing, GLUCAGON-LIKE PEPTIDE-1, CHD Exome+ Consortium, Neurology Working Group of the Cohorts for Heart, General Medicine, 11 Medical And Health Sciences, RANDOMIZED CONTROLLED-TRIAL, 3. Good health, Coronary Disease/genetics, 5-HT2C/genetics, CVD50 consortium, Drug development, Medicine, Research & Experimental, EPIC-InterAct, Public Health, Life Sciences & Biomedicine, INCRETIN-BASED THERAPIES, Receptor, Serotonin, RM, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), Genotype, Dipeptidyl Peptidase 4, CB2/genetics, TYPE-2 DIABETES-MELLITUS, 030209 endocrinology & metabolism, Article, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Sodium-Glucose Transporter 1, BETA-CELL FUNCTION, Diabetes mellitus, Diabetes Mellitus, Journal Article, medicine, Humans, Sodium-Glucose Transporter 1/genetics, Obesity, Cannabinoid, Alleles, Science & Technology, business.industry, Alzheimer’s Disease Genetics Consortium, Glucagon-Like Peptide-1 Receptor/genetics, GERAD_EC Consortium, Cell Biology, 06 Biological Sciences, medicine.disease, R1, Human genetics, CARDIOGRAM Exome Consortium, Clinical trial, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Aging Research in Genomic Epidemiology (CHARGE), business, RC, Pancreatic Cancer Cohort Consortium
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

Published
2016
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40. Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others.

Author

Bartlett JM, Bayani J, Marshall A, Dunn JA, Campbell A, Cunningham C, Sobol MS, Hall PS, Poole CJ, Cameron DA, Earl HM, Rea DW, Macpherson IR, Canney P, Francis A, McCabe C, Pinder SE, Hughes-Davies L, Makris A, and Stein RC

Subjects
Adult, Aged, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms chemistry, Breast Neoplasms pathology, Clinical Decision-Making, Confidence Intervals, Female, Humans, Lymphatic Metastasis, Middle Aged, Nomograms, Predictive Value of Tests, Prognosis, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Risk Assessment methods, Tumor Burden, Breast Neoplasms classification, Breast Neoplasms drug therapy, Decision Support Techniques, Neoplasm Recurrence, Local drug therapy
Abstract

Background: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population., Methods: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna., Results: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors., Conclusions: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2016
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41. Common germline polymorphisms associated with breast cancer-specific survival.

Author

Pirie A, Guo Q, Kraft P, Canisius S, Eccles DM, Rahman N, Nevanlinna H, Chen C, Khan S, Tyrer J, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Dunning AM, Shah M, Czene K, Darabi H, Eriksson M, Lambrechts D, Weltens C, Leunen K, van Ongeval C, Nordestgaard BG, Nielsen SF, Flyger H, Rudolph A, Seibold P, Flesch-Janys D, Blomqvist C, Aittomäki K, Fagerholm R, Muranen TA, Olsen JE, Hallberg E, Vachon C, Knight JA, Glendon G, Mulligan AM, Broeks A, Cornelissen S, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Hopper JL, Tsimiklis H, Apicella C, Southey MC, Cross SS, Reed MW, Giles GG, Milne RL, McLean C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Hooning MJ, Hollestelle A, Martens JW, van den Ouweland AM, Marme F, Schneeweiss A, Yang R, Burwinkel B, Figueroa J, Chanock SJ, Lissowska J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Brenner H, Butterbach K, Holleczek B, Kataja V, Kosma VM, Hartikainen JM, Li J, Brand JS, Humphreys K, Devilee P, Tollenaar RA, Seynaeve C, Radice P, Peterlongo P, Manoukian S, Ficarazzi F, Beckmann MW, Hein A, Ekici AB, Balleine R, Phillips KA, Benitez J, Zamora MP, Perez JI, Menéndez P, Jakubowska A, Lubinski J, Gronwald J, Durda K, Hamann U, Kabisch M, Ulmer HU, Rüdiger T, Margolin S, Kristensen V, Nord S, Evans DG, Abraham J, Earl H, Poole CJ, Hiller L, Dunn JA, Bowden S, Yang R, Campa D, Diver WR, Gapstur SM, Gaudet MM, Hankinson S, Hoover RN, Hüsing A, Kaaks R, Machiela MJ, Willett W, Barrdahl M, Canzian F, Chin SF, Caldas C, Hunter DJ, Lindstrom S, Garcia-Closas M, Couch FJ, Chenevix-Trench G, Mannermaa A, Andrulis IL, Hall P, Chang-Claude J, Easton DF, Bojesen SE, Cox A, Fasching PA, Pharoah PD, and Schmidt MK

Subjects
Female, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Prognosis, Breast Neoplasms genetics, Breast Neoplasms mortality, Germ Cells metabolism, Polymorphism, Single Nucleotide
Abstract

Introduction: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium., Methods: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect., Results: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease., Conclusions: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

Published
2015
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