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2. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial

Author

Powell, M.A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L.M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M.A., Segev, Y., Gill, S.E., Gennigens, C., Sebastianelli, A., Shahin, M.S., Pothuri, B., Monk, B.J., Buscema, J., Coleman, R.L., Slomovitz, B.M., Ring, K.L., Herzog, T.J., Balas, M.M., Grimshaw, M., Stevens, S., Lai, D.W., McCourt, C., and Mirza, M.R.

Published
2024
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3. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author

Vergote, I., Ausems, M., Brasiuniene, B., Brenton, J., Büttner, R., Colombo, N., González-Martín, A., Harter, P., Lambrechts, D., Lorusso, D., Madry, R., Mirza, M.R., Pujol, P., Ray-Coquard, I., Abreu, M., Balboni, S., Banerjee, S., Barberis, M., Barretina Ginesta, M.P., Baurain, J.-F., Bignami, M., Bjorge, L., Blecharz, P., Bruchim, I., Capilna, M., Cerana, N., Cicchetti, A., Collins, D., Concin, N., D’Incalci, M., Davidson, B., de la Motte Rouge, T., De Iaco, P., Demirkiran, F., Denys, H., Doerk, T., Dorum, A., Ferrero, A., Fidalgo, A.P., Genuardi, M., Gladieff, L., Glasspool, R., Grimm, C., Gultekin, M., Hahnen, E., Hasenburg, A., Hegmane, A., Heinzelmann, V., Hogdall, E., Janavicius, R., Jarmalaite, S., Kalachand, R., Kaneva, R., Kilickap, S., Kocian, R., Kolencik, D., Kristeleit, R., Kryzhanivska, A., Leary, A., Lemley, B., Ligtenberg, M., López-Guerrero, J.A., Lord, C.J., Avall-Lundqvist, E., Maenpaa, J., Mahner, S., Marmé, F., Marth, C., McNeish, I., Merkelbach-Bruse, S., Mourits, M., Normanno, N., Oaknin, A., Ojamaa, K., Papdimitriou, C., Penault-Llorca, F., Perrone, A.M., Pignata, S., Pikarsky, E., Rouleau, E., Rubio, M., Sapino, A., Schmalfeldt, B., Sehouli, J., Shapira, R., Steffensen, K.D., Sukhin, V., Syrios, J., Szallasi, Z., Taskiran, C., Terzic, M., Tischkowitz, M., Toth, I., Van de Vijver, K., Vardar, M.A., Wasag, B., Wimberger, P., Witteveen, E., Brenton, J.D., and Ausems, M.G.E.M.

Published
2022
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4. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial

Author

Powell, M. A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L. M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M. A., Segev, Y., Gill, S. E., Gennigens, C., Sebastianelli, A., Shahin, M. S., Pothuri, B., Monk, B. J., Buscema, J., Coleman, R. L., Slomovitz, B. M., Ring, K. L., Herzog, T. J., Balas, M. M., Grimshaw, M., Stevens, S., Lai, D. W., McCourt, C., Mirza, M. R., Powell, M. A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L. M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M. A., Segev, Y., Gill, S. E., Gennigens, C., Sebastianelli, A., Shahin, M. S., Pothuri, B., Monk, B. J., Buscema, J., Coleman, R. L., Slomovitz, B. M., Ring, K. L., Herzog, T. J., Balas, M. M., Grimshaw, M., Stevens, S., Lai, D. W., McCourt, C., and Mirza, M. R.

Abstract

Background: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. Patients and methods: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1: 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. Results: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis. Conclusions: Dostarlimab in combination with carboplatin–paclitaxel

Published
2024

8. 731P Post-progression survival outcomes in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC) in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial who received follow-up immunotherapy

Author

Mirza, M.R., Mathews, C., Gilbert, L., Bjorge, L., Ring, K., Pishchyk, M.M., Pennington, K., Segev, Y., Powell, M.A., Van Gorp, T., Bender, D., Schneider, K., Miller, R., Armstrong, A., Canturia, G., Gogoi, R., Antony, G., Stevens, S., Valabrega, G., and Landrum, L.M.

Published
2024
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9. Author Correction: Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock

Author

Barrett, J James E, Barrett, J, Herzog, C, Kim, Y, Bartlett, T, Jones, A, Evans, I, Cibula, D, Zikan, M, Bjørge, L, Harbeck, N, Colombo, N, Howell, S, Rådestad, A, Gemzell-Danielsson, K, Widschwendter, M, Barrett, J James E, Herzog, Chiara, Kim, Yoo-Na, Bartlett, Thomas E, Jones, Allison, Evans, Iona, Cibula, David, Zikan, Michal, Bjørge, Line, Harbeck, Nadia, Colombo, Nicoletta, Howell, Sacha J, Rådestad, Angelique Flöter, Gemzell-Danielsson, Kristina, Widschwendter, Martin, Barrett, J James E, Barrett, J, Herzog, C, Kim, Y, Bartlett, T, Jones, A, Evans, I, Cibula, D, Zikan, M, Bjørge, L, Harbeck, N, Colombo, N, Howell, S, Rådestad, A, Gemzell-Danielsson, K, Widschwendter, M, Barrett, J James E, Herzog, Chiara, Kim, Yoo-Na, Bartlett, Thomas E, Jones, Allison, Evans, Iona, Cibula, David, Zikan, Michal, Bjørge, Line, Harbeck, Nadia, Colombo, Nicoletta, Howell, Sacha J, Rådestad, Angelique Flöter, Gemzell-Danielsson, Kristina, and Widschwendter, Martin

Abstract

Following publication of the original article [1], it was brought to our attention that one of the references was incorrect. The text of the article reads: The general, epithelial and immune clocks are significantly, albeit weakly, correlated with two mitotic clocks, the pcgtAge score based on promoter CpGs at polycomb group target genes [24] and an alternative mitotic clock model recently developed using “solo-WCGWs” [25] The correct reference for citation 24 should be as follows: 24. Yang Z, Wong A, Kuh D, Paul DS, Rakyan VK, Leslie RD et al. Correlation of an epigenetic mitotic clock with cancer risk. Genome Biology 2016; 17: 205 Also, we wish to add an additional reference to that cited as citation 25. It has been brought to our attention that it would also be relevant to cite the following: 25. Teschendorff AE. A comparison of epigenetic mitotic-like clocks for cancer risk prediction. Genome Medicine 2020; 12: 56 We apologize for the previous errors in the reference list.

Published
2022

10. The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Author

Barrett, J, Herzog, C, Jones, A, Leavy, O, Evans, I, Knapp, S, Reisel, D, Nazarenko, T, Kim, Y, Franchi, D, Ryan, A, Franks, J, Bjørge, L, Zikan, M, Cibula, D, Harbeck, N, Colombo, N, Dudbridge, F, Jones, L, Sundström, K, Dillner, J, Rådestad, A, Gemzell-Danielsson, K, Pashayan, N, Widschwendter, M, Barrett, James E, Herzog, Chiara, Jones, Allison, Leavy, Olivia C, Evans, Iona, Knapp, Susanne, Reisel, Daniel, Nazarenko, Tatiana, Kim, Yoo-Na, Franchi, Dorella, Ryan, Andy, Franks, Joanna, Bjørge, Line, Zikan, Michal, Cibula, David, Harbeck, Nadia, Colombo, Nicoletta, Dudbridge, Frank, Jones, Louise, Sundström, Karin, Dillner, Joakim, Rådestad, Angelique Flöter, Gemzell-Danielsson, Kristina, Pashayan, Nora, Widschwendter, Martin, Barrett, J, Herzog, C, Jones, A, Leavy, O, Evans, I, Knapp, S, Reisel, D, Nazarenko, T, Kim, Y, Franchi, D, Ryan, A, Franks, J, Bjørge, L, Zikan, M, Cibula, D, Harbeck, N, Colombo, N, Dudbridge, F, Jones, L, Sundström, K, Dillner, J, Rådestad, A, Gemzell-Danielsson, K, Pashayan, N, Widschwendter, M, Barrett, James E, Herzog, Chiara, Jones, Allison, Leavy, Olivia C, Evans, Iona, Knapp, Susanne, Reisel, Daniel, Nazarenko, Tatiana, Kim, Yoo-Na, Franchi, Dorella, Ryan, Andy, Franks, Joanna, Bjørge, Line, Zikan, Michal, Cibula, David, Harbeck, Nadia, Colombo, Nicoletta, Dudbridge, Frank, Jones, Louise, Sundström, Karin, Dillner, Joakim, Rådestad, Angelique Flöter, Gemzell-Danielsson, Kristina, Pashayan, Nora, and Widschwendter, Martin

Abstract

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

Published
2022

14. LBA28 A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial

Author

Mirza, M.R., primary, Bjørge, L., additional, Marmé, F., additional, DePont Christensen, R., additional, Gil-Martin, M., additional, Auranen, A., additional, Ataseven, B., additional, Rubio, M.J., additional, Salutari, V., additional, Lund, B., additional, Runnebaum, I., additional, Redondo, A., additional, Lindemann, K., additional, Trillsch, F., additional, Barretina Ginesta, M.P., additional, Roed, H., additional, Løhndorf, J., additional, Nyvang, G-B., additional, and Sehouli, J., additional

Published
2020
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16. A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC):NSGO-PALEO / ENGOT-EN3 trial

Author

Mirza, M.R., Bjørge, L., Marmé, F., Christensen, R. DePont, Gil-Martin, M., Auranen, A., Ataseven, B., Rubio, M.J., Salutari, V., Lund, B., Runnebaum, I., Redondo, A., Lindemann, K., Trillsch, F., Ginesta, M.P. Barretina, Roed, H., Løhndorf, J., Nyvang, G-B., and Sehouli, J.

Published
2020
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17. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

Author

du Bois, A, Kristensen, G, Ray-Coquard, I, Reuss, A, Pignata, S, Colombo, N, Denison, U, Vergote, I, Del Campo JM, Ottevanger, P, Heubner, M, Minarik, T, Sevin, E, de Gregorio, N, Bidziński, M, Pfisterer, J, Malander, S, Hilpert, F, Mirza, Mr, Scambia, G, Meier, W, Nicoletto, Mo, Bjørge, L, Lortholary, A, Sailer, Mo, Merger, M, Harter, P, AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium: Università degli Studi di Torino ITA, Ferrero, A, Et, Al, du Bois, A, Kristensen, G, Ray Coquard, I, Reuss, A, Pignata, S, Colombo, N, Denison, U, Vergote, I, Del Campo, J, Ottevanger, P, Heubner, M, Minarik, T, Sevin, E, de Gregorio, N, Bidziński, M, Pfisterer, J, Malander, S, Hilpert, F, Mirza, M, Scambia, G, Meier, W, Nicoletto, M, Bjørge, L, Lortholary, A, Sailer, M, Merger, M, and Harter, P

Subjects
0301 basic medicine, Indoles, Clinical Trial, Phase III, Medizin, ovarian cancer nintedanib angiogenesis inhibitor chemotherapy ENGOT clinical trial, Gastroenterology, Carboplatin, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Medicine, Peritoneal Neoplasms, Aged, 80 and over, Ovarian Neoplasms, education.field_of_study, Medicine (all), Research Support, Non-U.S. Gov't, Anemia, Cytoreduction Surgical Procedures, Middle Aged, Intention to Treat Analysis, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Multicenter Study, Oncology, Tolerability, 030220 oncology & carcinogenesis, Randomized Controlled Trial, Disease Progression, Female, Nintedanib, medicine.drug, Adult, Diarrhea, medicine.medical_specialty, Neutropenia, Paclitaxel, Bevacizumab, Population, Placebo, Disease-Free Survival, Young Adult, 03 medical and health sciences, Double-Blind Method, Internal medicine, Journal Article, Fallopian Tube Neoplasms, Humans, Progression-free survival, education, Response Evaluation Criteria in Solid Tumors, Aged, Neoplasm Staging, business.industry, Carcinoma, medicine.disease, Thrombocytopenia, Surgery, Settore MED/40 - GINECOLOGIA E OSTETRICIA, 030104 developmental biology, chemistry, business, Febrile neutropenia
Abstract

BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.FUNDING: Boehringer Ingelheim.

Published
2016
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21. CD24-targeted intraoperative fluorescence image-guided surgery leads to improved cytoreduction of ovarian cancer in a preclinical orthotopic surgical model

Author

Kleinmanns, K. (Katrin), Fosse, V. (Vibeke), Davidson, B. (B.), de Jalón, E.G. (Elvira García), Tenstad, O. (Olav), Bjørge, L. (Line), McCormack, E. (Emmet), Kleinmanns, K. (Katrin), Fosse, V. (Vibeke), Davidson, B. (B.), de Jalón, E.G. (Elvira García), Tenstad, O. (Olav), Bjørge, L. (Line), and McCormack, E. (Emmet)

Abstract

Background: The completeness of resection is a key prognostic indicator in patients with ovarian cancer, and the application of tumour-targeted fluorescence image-guided surgery (FIGS) has led to improved detection of peritoneal metastases during cytoreductive surgery. CD24 is highly expressed in ovarian cancer and has been shown to be a suita

Published
2020
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22. Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer

Author

Ray-Coquard, I, Cibula, D, Mirza, M, Reuss, A, Ricci, C, Colombo, N, Koch, H, Goffin, F, González-Martin, A, Ottevanger, P, Baumann, K, Bjørge, L, Lesoin, A, Burges, A, Rosenberg, P, Gropp-Meier, M, Harrela, M, Harter, P, Frenel, J, Minarik, T, Pisano, C, Hasenburg, A, Merger, M, du Bois, A, Ray-Coquard, Isabelle, Cibula, David, Mirza, Mansoor R, Reuss, Alexander, Ricci, Caterina, Colombo, Nicoletta, Koch, Horst, Goffin, Frédéric, González-Martin, Antonio, Ottevanger, Petronella B, Baumann, Klaus, Bjørge, Line, Lesoin, Anne, Burges, Alexander, Rosenberg, Per, Gropp-Meier, Martina, Harrela, Maija, Harter, Philipp, Frenel, Jean-Sébastien, Minarik, Tomas, Pisano, Carmela, Hasenburg, Annette, Merger, Michael, du Bois, Andreas, Ray-Coquard, I, Cibula, D, Mirza, M, Reuss, A, Ricci, C, Colombo, N, Koch, H, Goffin, F, González-Martin, A, Ottevanger, P, Baumann, K, Bjørge, L, Lesoin, A, Burges, A, Rosenberg, P, Gropp-Meier, M, Harrela, M, Harter, P, Frenel, J, Minarik, T, Pisano, C, Hasenburg, A, Merger, M, du Bois, A, Ray-Coquard, Isabelle, Cibula, David, Mirza, Mansoor R, Reuss, Alexander, Ricci, Caterina, Colombo, Nicoletta, Koch, Horst, Goffin, Frédéric, González-Martin, Antonio, Ottevanger, Petronella B, Baumann, Klaus, Bjørge, Line, Lesoin, Anne, Burges, Alexander, Rosenberg, Per, Gropp-Meier, Martina, Harrela, Maija, Harter, Philipp, Frenel, Jean-Sébastien, Minarik, Tomas, Pisano, Carmela, Hasenburg, Annette, Merger, Michael, and du Bois, Andreas

Abstract

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

Published
2020

23. Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer

Author

Ray-Coquard, I., Cibula, D., Mirza, M.R., Reuss, A., Ricci, C., Colombo, N., Koch, H., Goffin, F., González-Martin, A., Ottevanger, P.B., Baumann, K., Bjørge, L., Lesoin, A., Burges, A., Rosenberg, Per, Gropp-Meier, M., Harrela, M., Harter, P., Frenel, J.-S., Minarik, T., Pisano, C., Hasenburg, A., Merger, M., du, Bois A., Ray-Coquard, I., Cibula, D., Mirza, M.R., Reuss, A., Ricci, C., Colombo, N., Koch, H., Goffin, F., González-Martin, A., Ottevanger, P.B., Baumann, K., Bjørge, L., Lesoin, A., Burges, A., Rosenberg, Per, Gropp-Meier, M., Harrela, M., Harter, P., Frenel, J.-S., Minarik, T., Pisano, C., Hasenburg, A., Merger, M., and du, Bois A.

Abstract

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with amp;gt;1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports. © 2019 UICC, Funding agencies: AGO; Boehringer Ingelheim, Ingelheim, GermanyBoehringer Ingelheim

Published
2020
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25. Editorial Acknowledgment

Author

Aarvak, T., Abedi-Valugerdi, M., Abrahamsen, T., Akdis, C., Akuffo, H.O., Alarcon-Riquelme, M., Andersen, P., Arstila, P., Austgulen, R., Baecker-Allan, C., Baggiolini, M., Baker, B.S., Bakke, O., Bakken, V., Barclay, A.N., Bemark, M., Benestad, H.B., Berzins, K., Bjerkvik, R., Bjørge, L., Bland, P., Bolstad, A.I., Born, W., Bowman, S., Brinchmann, J., Britton, S., Brokstad, K.A., Brunet, L.R., Bruserud, Ø., Cardona, P.J., Ceyppens, J.L., Cirino, G., Cohn, M., Cox, R.J., Cunliffe, J., Dahlgren, U., Dellacasagrande, J., Ditzel, H., Dobryszycka, E., Dyrhol-Riise, A.M., Edwards, J.C., Egeland, T., Elsayed, S., Eray, M., Erb, K.J., Esch, T., Eugen-Olsen, J., Everse, L.A., Fagerhol, M., Farstad, I., Feldmann, M., Fernandez, C., Fleck, M., Franksson, R., Freitas, A., Garred, P., Gidlund, M., Gilhus, N.E., Goldbach-Mansky, R., Gordon, J., Gordon, T., Grandien, A., Gregerson, P., Grewal, H., Hakulinen, J., Halstensen, T., Haneberg, B., Hanej, S.H.E., Hansen, T., Harley, J.B., Haukenes, G., Hengartner, H., Henz, B.M., Holen, E., Hurme, M., Husby, G., Husby, S., Hörnqvist-Hultgren, E., Haaheim, L.R., Isenberg, D., Jahnson, F., Jakobsen, H., James, J.A., Jansson, J.O., Jarva, H., Jeansson, S., Johannessen, A.C., Johansen, F.E., Julkunen, I., Kalland, K.H., Kaye, J., Kazatchkine, M., Kihlström, E., Kohler, L., Konttinen, Y., Kotenko, S., Koutzov, S., Krammer, P., Kristoffersen, E., Kunzendorf, U., Lachmann, P., Langman, R., Langner, J., Lanzavecchia, L., Lappalainen, M., Laskay, T., Lea, T., Lefvert, A.K., Lehmann, A.C., Louka, A, Lúdviksson, B.R., Mariette, X., Marion, T., Marker-Herrmann, E., Mattsson, R., McAdam, S., Mellbye, O.J., Mellgren, G., Mellgren, S.I., Mestecky, J., Michaelsen, T., Michalek, S., Miettinen, A., Moestrup, S.K., Moretta, A., Moser, M., Mountz, J., Moutsopoulos, H., Munthe, L.A., Mustafa, T., Myrmel, H., Nannemark, G., Netea, M.G., Nilsen, R., Notarangelo, L.D., Ögmundsdóttir, H., Olsson, I., Olweus, J., Osland, A., Paludan, S.R., Parsons, K.R., Patarroyo, M., Paul, W.E., Perlman, P., Pollock, J.M., Puolakkainen, M., Quale, A., Rajewsky, K., Raman, C., Reichlin, M., Renkonen, R., Rese Shadidi, K., Ricciardi-Castagnoli, P., Rickinson, A.B., Ringdén, O., Risto, R., Rodinov, D., Rosenkrands, I., Rottenberg, M., Russel, M., Rygaard, J., Rødahl, E., Röllinghof, M., Sandberg, M., Schenk, K., Seppälä, I., Shevach, E., Shortman, K., Siegrist, C.A., Sigurdardóttir, S., Silvennoinen, O., Sinigaglia, F., Sistonen, L., Skarstein, K., Skogh, T., Smith, E., Spurkland, A., Stendahl, O., Sugden, B., Suri-Payer, E., Svennerholm, A.M., Szodoray, P., Theofilopoulos, A., Thorley-Lawson, D.A., Timonen, T., Trowsdale, J., Tuomo, T., Ulmer, A.J., Ulvestad, E., Ulvik, R., Vaerman, J.P., van, der Merwe J.P., van Eden, W., Vedeler, C., Vintermyr, O.K., Vyse, J., Wahlgren, M., Wahren-Herlenius, M., Walsh, L.J., Weetman, A.P., Westermark, P., Wiker, H., Yang, J., Yewdell, J.W., Youinou, P., and Zouali, M.

Published
2002

29. Toll-Like Receptor-3 expression by maternal and fetal cells at the maternal-fetal interface is associated with development of preeclampsia

Author

Gierman, L.M., primary, Silva, G.B., additional, Pervaiz, Z., additional, Rakner, J., additional, Mundal, S.B., additional, Thaning, A.J., additional, Elschot, M., additional, Ostrop, J., additional, Dahlberg, U., additional, Thomsen, L.C.V., additional, Bjørge, L., additional, and Iversen, A.C., additional

Published
2019
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30. Erratum: Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature communications (2019) 10 1 (431))

Author

Jiang, X. (Xia), Finucane, H.K. (Hilary K.), Schumacher, F.R. (Fredrick R), Schmit, S.L. (Stephanie L.), Tyrer, J.P. (Jonathan P.), Han, Y. (Younghun), Michailidou, K. (Kyriaki), Lesseur, C. (Corina), Kuchenbaecker, K.B. (Karoline), Dennis, J. (Joe), Conti, G. (Giario), Casey, G. (Graham), Gaudet, M.M. (Mia M.), Huyghe, J.R. (Jeroen R.), Albanes, D. (Demetrius), Aldrich, M.C. (Melinda), Andrew, A.S. (Angeline S.), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Antonenkova, N.N. (Natalia N.), Arnold, S.M. (Susanne M.), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Bandera, E.V. (Elisa), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Batra, J. (Jyotsna), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Benlloch, S. (Sara), Berchuck, A. (Andrew), Berndt, S.I. (Sonja), Bickeböller, H. (Heike), Bien, S.A. (Stephanie A.), Blomqvist, C. (Carl), Boccia, S. (Stefania), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brenton, J.D. (James D.), Brook, R.H., Brunet, J. (Joan), Brunnström, H. (Hans), Buchanan, D.D. (Daniel D.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Cadoni, G. (Gabriella), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Campbell, P.T. (Peter T.), Cancel-Tassin, G. (Géraldine), Cannon-Albright, L.A. (Lisa), Campa, D. (Daniele), Caporaso, N.E. (Neil), Carvalho, A.L. (André L), Chan, A.T. (Andrew T.), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, C. (Chu), Christiani, D.C. (David C.), Claes, K.B.M. (Kathleen B M), Claessens, F. (Frank), Clements, J. (Judith), Collée, J.M. (J Margriet), Correa, M.C. (Marcia Cruz), Couch, F.J. (Fergus), Cox, A. (Angela), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), DeFazio, A. (Anna), Devilee, P. (Peter), Diez, O. (Orland), Gago-Dominguez, M. (Manuela), Donovan, J.L. (Jenny L.), Dörk, T. (Thilo), Duell, E.J. (Eric), Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D. (Diana), Edlund, C.K. (Christopher), Edwards, D.R.V. (Digna R Velez), Ellberg, C. (Carolina), Evans, D.G. (D Gareth), Fasching, P.A. (Peter), Ferris, R.L. (Robert L.), Liloglou, T. (Triantafillos), Figueiredo, J.C. (Jane C.), Fletcher, O. (Olivia), Fortner, R.T. (Renée T), Fostira, F. (Florentia), Franceschi, S. (Silvia), Friedman, E. (Eitan), Gallinger, S. (Steve), Ganz, P.A. (Patricia), Garber, J. (Judy), García-Sáenz, J.A. (José A), Gayther, S.A. (Simon), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D.E. (David E.), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Goodman, G. (Gary), Grankvist, K. (Kjell), Greene, M.H. (Mark H.), Grönberg, H. (Henrik), Gronwald, J. (Jacek), Guénel, P. (Pascal), Håkansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hamdy, F. (Freddie), Hamilton, R.J. (Robert J.), Hampe, J. (Jochen), Haugen, A. (Aage), Heitz, F. (Florian), Herrero, R. (Rolando), Hillemanns, P. (Peter), Hoffmeister, M. (Michael), Høgdall, E. (Estrid), Hong, Y.-C. (Yun-Chul), Hopper, J.L. (John), Houlston, R. (Richard), Hulick, P.J. (Peter J.), Hunter, D.J. (David), Huntsman, D.G. (David G.), Idos, G. (Gregory), Imyanitov, E.N. (Evgeny), Ingles, S.A. (Sue), Isaacs, C. (Claudine), Jakubowska, A. (Anna), James, M. (Margaret), Jenkins, M.A. (Mark A.), Johansson, M. (Mattias), Johansson, M. (Mikael), John, E.M. (Esther), Joshi, A.D. (Amit D.), Kaneva, R. (Radka), Karlan, B.Y. (Beth), Kelemen, L.E. (Linda E.), Kühl, T. (Tabea), Khaw, K.-T. (Kay-Tee), Khusnutdinova, E.K. (Elza), Kibel, A. (Adam), Kiemeney, L.A. (Lambertus A.), Kim, J. (Jongoh), Kjaer, M. (Michael), Knight, J.A. (Julia), Kogevinas, M. (Manolis), Kote-Jarai, Z., Koutros, S. (Stella), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Lacko, M. (Martin), Lam, S. (Stephan), Lambrechts, D. (Diether), Landi, M.T. (Maria Teresa), Lazarus, P. (Philip), Le, N.D. (Nhu D.), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lenz, H.-J. (Heinz-Josef), Leslie, G. (Goska), Lessel, D. (Davor), Lester, J. (Jenny), Levine, D.A. (Douglas), Li, L. (Li), Li, C.I. (Christopher I.), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Liu, G. (Geoffrey), Loupakis, F. (Fotios), Lubinski, J. (Jan), Maehle, L., Maier, C. (Christiane), Mannermaa, A. (Arto), Le Marchand, L. (Loic), Margolin, S. (Sara), May, T. (Taymaa), McGuffog, L. (Lesley), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, A. (Austin), Milne, R.L. (Roger), MacInnis, R.J. (Robert J.), Modugno, F. (Francesmary), Montagna, M. (Marco), Moreno, V. (Víctor), Moysich, K.B. (Kirsten), Mucci, L. (Lorelei), Muir, K. (Kenneth), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neal, D. (David), Ness, A.R. (Andrew R.), Neuhausen, S.L. (Susan L.), Nevanlinna, H. (Heli), Newcomb, P. (Polly), Newcomb, L.F. (Lisa F.), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Offit, K. (Kenneth), Olah, E. (Edith), Olama, A.A.A. (Ali Amin Al), Olopade, O.I. (Olofunmilayo), Olshan, A.F. (Andrew F.), Olsson, H. (Håkan), Osorio, A. (Ana), Pandha, H. (Hardev), Park, J.Y. (Jong Y.), Pashayan, N. (Nora), Parsons, M. (Marilyn), Pejovic, T. (Tanja), Penney, K.L. (Kathryn L.), Peters, W.H.M. (Wilbert), Phelan, C. (Catherine), Phipps, A.I. (Amanda I.), Plaseska-Karanfilska, D. (Dijana), Pring, M. (Miranda), Prokofyeva, D. (Darya), Radice, P. (Paolo), Stefansson, K. (Kari), Ramus, S.J. (Susan), Raskin, L. (Leon), Rennert, G. (Gad), Rennert, H.S. (Hedy S.), Rensburg, E.J. (Elizabeth) van, Riggan, M.J. (Marjorie J.), Risch, H.A. (Harvey A.), Risch, A. (Angela), Roobol, M.J. (Monique J.), Rosenstein, B.S. (Barry S.), Rossing, M.A. (Mary Anne), De Ruyck, K. (Kim), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Sawyer, E.J. (Elinor J.), Schabath, M.B. (Matthew), Schleutker, J. (Johanna), Schmidt, M.K. (Marjanka), Setiawan, V.W. (V Wendy), Shen, H. (Hongbing), Siegel, E.M. (Erin M.), Sieh, W. (Weiva), Singer, C.F. (Christian), Slattery, M.L. (Martha L.), Sorensen, K.D. (Karina Dalsgaard), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stanford, J.L. (Janet L.), Stevens, V.L. (Victoria L.), Stintzing, S. (Sebastian), Stone, J. (Jennifer), Sundfeldt, K. (Karin), Sutphen, R. (Rebecca), Swerdlow, A.J. (Anthony ), Tajara, E.H. (Eloiza H.), Tangen, C.M. (Catherine M.), Tardón, A. (Adonina), Taylor, J.A. (Jack A.), Teare, M.D. (M Dawn), Teixeira, P.J., Terry, M.B. (Mary Beth), Terry, K.L. (Kathryn L.), Thibodeau, S.N. (Stephen), Thomassen, M. (Mads), Bjørge, L. (Line), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Torres, D. (Diana), Townsend, P.A. (Paul A.), Travis, S.P.L. (Simon), Tung, N. (Nadine), Tworoger, S. (Shelley), Ulrich, C. (Cornelia), Usmani, N. (Nawaid), Vachon, C. (Celine), Van Nieuwenhuysen, E. (Els), Vega, A. (Ana), Aguado-Barrera, M.E. (Miguel Elías), Wang, Q. (Qin), Webb, P. (Penny), Weinberg, C.R. (Clarice R.), Weinstein, S. (Stephanie), Weissler, M.C. (Mark C.), Weitzel, J.N. (Jeffrey), West, C.M.L. (Catharine M L), White, E. (Emily), Whittemore, A.S. (Alice), Wichmann, H.-E. (H-Erich), Wiklund, F. (Fredrik), Winqvist, R. (Robert), Wolk, K. (Kerstin), Woll, P.J. (Penella J), Woods, M.O. (Michael), Wu, A.H. (Anna H.), Wu, X. (Xifeng), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zienolddiny, S. (Shanbeh), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Lane, J.M. (Jacqueline M.), Saxena, R. (Richa), Thomas, D.C. (Duncan), Hung, R.J. (Rayjean J.), Diergaarde, B. (Brenda), McKay, J. (James), Peters, U. (Ulrike), Hsu, L. (Li), García-Closas, M. (Montserrat), Eeles, R.A. (Rosalind A.), Chenevix-Trench, G. (Georgia), Brennan, P.J. (Paul J.), Haiman, C.A. (Christopher), Simard, J. (Jacques), Easton, D.F. (Douglas), Gruber, S.B. (Stephen), Pharoah, P.D.P. (Paul), Price, A.L. (Alkes L.), Pasaniuc, B. (Bogdan), Amos, C.I. (Christopher I.), Kraft, P. (Peter), Lindström, S. (Sara), Jiang, X. (Xia), Finucane, H.K. (Hilary K.), Schumacher, F.R. (Fredrick R), Schmit, S.L. (Stephanie L.), Tyrer, J.P. (Jonathan P.), Han, Y. (Younghun), Michailidou, K. (Kyriaki), Lesseur, C. (Corina), Kuchenbaecker, K.B. (Karoline), Dennis, J. (Joe), Conti, G. (Giario), Casey, G. (Graham), Gaudet, M.M. (Mia M.), Huyghe, J.R. (Jeroen R.), Albanes, D. (Demetrius), Aldrich, M.C. (Melinda), Andrew, A.S. (Angeline S.), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Antonenkova, N.N. (Natalia N.), Arnold, S.M. (Susanne M.), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Bandera, E.V. (Elisa), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Batra, J. (Jyotsna), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Benlloch, S. (Sara), Berchuck, A. (Andrew), Berndt, S.I. (Sonja), Bickeböller, H. (Heike), Bien, S.A. (Stephanie A.), Blomqvist, C. (Carl), Boccia, S. (Stefania), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brenton, J.D. (James D.), Brook, R.H., Brunet, J. (Joan), Brunnström, H. (Hans), Buchanan, D.D. (Daniel D.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Cadoni, G. (Gabriella), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Campbell, P.T. (Peter T.), Cancel-Tassin, G. (Géraldine), Cannon-Albright, L.A. (Lisa), Campa, D. (Daniele), Caporaso, N.E. (Neil), Carvalho, A.L. (André L), Chan, A.T. (Andrew T.), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, C. (Chu), Christiani, D.C. (David C.), Claes, K.B.M. (Kathleen B M), Claessens, F. (Frank), Clements, J. (Judith), Collée, J.M. (J Margriet), Correa, M.C. (Marcia Cruz), Couch, F.J. (Fergus), Cox, A. (Angela), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), DeFazio, A. (Anna), Devilee, P. (Peter), Diez, O. (Orland), Gago-Dominguez, M. (Manuela), Donovan, J.L. (Jenny L.), Dörk, T. (Thilo), Duell, E.J. (Eric), Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D. (Diana), Edlund, C.K. (Christopher), Edwards, D.R.V. (Digna R Velez), Ellberg, C. (Carolina), Evans, D.G. (D Gareth), Fasching, P.A. (Peter), Ferris, R.L. (Robert L.), Liloglou, T. (Triantafillos), Figueiredo, J.C. (Jane C.), Fletcher, O. (Olivia), Fortner, R.T. (Renée T), Fostira, F. (Florentia), Franceschi, S. (Silvia), Friedman, E. (Eitan), Gallinger, S. (Steve), Ganz, P.A. (Patricia), Garber, J. (Judy), García-Sáenz, J.A. (José A), Gayther, S.A. (Simon), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D.E. (David E.), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Goodman, G. (Gary), Grankvist, K. (Kjell), Greene, M.H. (Mark H.), Grönberg, H. (Henrik), Gronwald, J. (Jacek), Guénel, P. (Pascal), Håkansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hamdy, F. (Freddie), Hamilton, R.J. (Robert J.), Hampe, J. (Jochen), Haugen, A. (Aage), Heitz, F. (Florian), Herrero, R. (Rolando), Hillemanns, P. (Peter), Hoffmeister, M. (Michael), Høgdall, E. (Estrid), Hong, Y.-C. (Yun-Chul), Hopper, J.L. (John), Houlston, R. (Richard), Hulick, P.J. (Peter J.), Hunter, D.J. (David), Huntsman, D.G. (David G.), Idos, G. (Gregory), Imyanitov, E.N. (Evgeny), Ingles, S.A. (Sue), Isaacs, C. (Claudine), Jakubowska, A. (Anna), James, M. (Margaret), Jenkins, M.A. (Mark A.), Johansson, M. (Mattias), Johansson, M. (Mikael), John, E.M. (Esther), Joshi, A.D. (Amit D.), Kaneva, R. (Radka), Karlan, B.Y. (Beth), Kelemen, L.E. (Linda E.), Kühl, T. (Tabea), Khaw, K.-T. (Kay-Tee), Khusnutdinova, E.K. (Elza), Kibel, A. (Adam), Kiemeney, L.A. (Lambertus A.), Kim, J. (Jongoh), Kjaer, M. (Michael), Knight, J.A. (Julia), Kogevinas, M. (Manolis), Kote-Jarai, Z., Koutros, S. (Stella), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Lacko, M. (Martin), Lam, S. (Stephan), Lambrechts, D. (Diether), Landi, M.T. (Maria Teresa), Lazarus, P. (Philip), Le, N.D. (Nhu D.), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Lenz, H.-J. (Heinz-Josef), Leslie, G. (Goska), Lessel, D. (Davor), Lester, J. (Jenny), Levine, D.A. (Douglas), Li, L. (Li), Li, C.I. (Christopher I.), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Liu, G. (Geoffrey), Loupakis, F. (Fotios), Lubinski, J. (Jan), Maehle, L., Maier, C. (Christiane), Mannermaa, A. (Arto), Le Marchand, L. (Loic), Margolin, S. (Sara), May, T. (Taymaa), McGuffog, L. (Lesley), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, A. (Austin), Milne, R.L. (Roger), MacInnis, R.J. (Robert J.), Modugno, F. (Francesmary), Montagna, M. (Marco), Moreno, V. (Víctor), Moysich, K.B. (Kirsten), Mucci, L. (Lorelei), Muir, K. (Kenneth), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Neal, D. (David), Ness, A.R. (Andrew R.), Neuhausen, S.L. (Susan L.), Nevanlinna, H. (Heli), Newcomb, P. (Polly), Newcomb, L.F. (Lisa F.), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Offit, K. (Kenneth), Olah, E. (Edith), Olama, A.A.A. (Ali Amin Al), Olopade, O.I. (Olofunmilayo), Olshan, A.F. (Andrew F.), Olsson, H. (Håkan), Osorio, A. (Ana), Pandha, H. (Hardev), Park, J.Y. (Jong Y.), Pashayan, N. (Nora), Parsons, M. (Marilyn), Pejovic, T. (Tanja), Penney, K.L. (Kathryn L.), Peters, W.H.M. (Wilbert), Phelan, C. (Catherine), Phipps, A.I. (Amanda I.), Plaseska-Karanfilska, D. (Dijana), Pring, M. (Miranda), Prokofyeva, D. (Darya), Radice, P. (Paolo), Stefansson, K. (Kari), Ramus, S.J. (Susan), Raskin, L. (Leon), Rennert, G. (Gad), Rennert, H.S. (Hedy S.), Rensburg, E.J. (Elizabeth) van, Riggan, M.J. (Marjorie J.), Risch, H.A. (Harvey A.), Risch, A. (Angela), Roobol, M.J. (Monique J.), Rosenstein, B.S. (Barry S.), Rossing, M.A. (Mary Anne), De Ruyck, K. (Kim), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Sawyer, E.J. (Elinor J.), Schabath, M.B. (Matthew), Schleutker, J. (Johanna), Schmidt, M.K. (Marjanka), Setiawan, V.W. (V Wendy), Shen, H. (Hongbing), Siegel, E.M. (Erin M.), Sieh, W. (Weiva), Singer, C.F. (Christian), Slattery, M.L. (Martha L.), Sorensen, K.D. (Karina Dalsgaard), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stanford, J.L. (Janet L.), Stevens, V.L. (Victoria L.), Stintzing, S. (Sebastian), Stone, J. (Jennifer), Sundfeldt, K. (Karin), Sutphen, R. (Rebecca), Swerdlow, A.J. (Anthony ), Tajara, E.H. (Eloiza H.), Tangen, C.M. (Catherine M.), Tardón, A. (Adonina), Taylor, J.A. (Jack A.), Teare, M.D. (M Dawn), Teixeira, P.J., Terry, M.B. (Mary Beth), Terry, K.L. (Kathryn L.), Thibodeau, S.N. (Stephen), Thomassen, M. (Mads), Bjørge, L. (Line), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Torres, D. (Diana), Townsend, P.A. (Paul A.), Travis, S.P.L. (Simon), Tung, N. (Nadine), Tworoger, S. (Shelley), Ulrich, C. (Cornelia), Usmani, N. (Nawaid), Vachon, C. (Celine), Van Nieuwenhuysen, E. (Els), Vega, A. (Ana), Aguado-Barrera, M.E. (Miguel Elías), Wang, Q. (Qin), Webb, P. (Penny), Weinberg, C.R. (Clarice R.), Weinstein, S. (Stephanie), Weissler, M.C. (Mark C.), Weitzel, J.N. (Jeffrey), West, C.M.L. (Catharine M L), White, E. (Emily), Whittemore, A.S. (Alice), Wichmann, H.-E. (H-Erich), Wiklund, F. (Fredrik), Winqvist, R. (Robert), Wolk, K. (Kerstin), Woll, P.J. (Penella J), Woods, M.O. (Michael), Wu, A.H. (Anna H.), Wu, X. (Xifeng), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zienolddiny, S. (Shanbeh), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Lane, J.M. (Jacqueline M.), Saxena, R. (Richa), Thomas, D.C. (Duncan), Hung, R.J. (Rayjean J.), Diergaarde, B. (Brenda), McKay, J. (James), Peters, U. (Ulrike), Hsu, L. (Li), García-Closas, M. (Montserrat), Eeles, R.A. (Rosalind A.), Chenevix-Trench, G. (Georgia), Brennan, P.J. (Paul J.), Haiman, C.A. (Christopher), Simard, J. (Jacques), Easton, D.F. (Douglas), Gruber, S.B. (Stephen), Pharoah, P.D.P. (Paul), Price, A.L. (Alkes L.), Pasaniuc, B. (Bogdan), Amos, C.I. (Christopher I.), Kraft, P. (Peter), and Lindström, S. (Sara)

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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31. Association between the cervicovaginal microbiome, BRCA1 mutation status, and risk of ovarian cancer: a case-control study

Author

Nené, N, Reisel, D, Leimbach, A, Franchi, D, Jones, A, Evans, I, Knapp, S, Ryan, A, Ghazali, S, Timms, J, Paprotka, T, Bjørge, L, Zikan, M, Cibula, D, Colombo, N, Widschwendter, M, Nené, Nuno R, Reisel, Daniel, Leimbach, Andreas, Franchi, Dorella, Jones, Allison, Evans, Iona, Knapp, Susanne, Ryan, Andy, Ghazali, Shohreh, Timms, John F, Paprotka, Tobias, Bjørge, Line, Zikan, Michal, Cibula, David, Colombo, Nicoletta, Widschwendter, Martin, Nené, N, Reisel, D, Leimbach, A, Franchi, D, Jones, A, Evans, I, Knapp, S, Ryan, A, Ghazali, S, Timms, J, Paprotka, T, Bjørge, L, Zikan, M, Cibula, D, Colombo, N, Widschwendter, M, Nené, Nuno R, Reisel, Daniel, Leimbach, Andreas, Franchi, Dorella, Jones, Allison, Evans, Iona, Knapp, Susanne, Ryan, Andy, Ghazali, Shohreh, Timms, John F, Paprotka, Tobias, Bjørge, Line, Zikan, Michal, Cibula, David, Colombo, Nicoletta, and Widschwendter, Martin

Abstract

Background: Various factors—including age, family history, inflammation, reproductive factors, and tubal ligation—modulate the risk of ovarian cancer. In this study, our aim was to establish whether women with, or at risk of developing, ovarian cancer have an imbalanced cervicovaginal microbiome. Methods: We did a case-control study in two sets of women aged 18–87 years in the Czech Republic, Germany, Italy, Norway, and the UK. The ovarian cancer set comprised women with epithelial ovarian cancer and controls (both healthy controls and those diagnosed with benign gynaecological conditions). The BRCA set comprised women with a BRCA1 mutation but without ovarian cancer and controls who were wild type for BRCA1 and BRCA2 (both healthy controls and those with benign gynaecological conditions). Cervicovaginal samples were gathered from all participants with the ThinPrep system and then underwent 16S rRNA gene sequencing. For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH, in the cervicovaginal microbiota. We grouped samples into those in which lactobacilli accounted for at least 50% of the species present (community type L) and those in which lactobacilli accounted for less than 50% of the species present (community type O). We assessed the adjusted association between BRCA1 status and ovarian cancer status and cervicovaginal microbiota community type, using a logistic regression model with a bias reduction method. Findings: Participants were recruited between Jan 2, 2016, and July 21, 2018. The ovarian cancer set (n=360) comprised 176 women with epithelial ovarian cancer, 115 healthy controls and 69 controls with benign gynaecological conditions. The BRCA set (n=220) included 109 women with BRCA1 mutations, 97 healthy controls wild type for BRCA1 and BRCA2 and 14 controls with a be

Published
2019

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

Author

Jiang, X, Finucane, Hk, Schumacher, Fr, Schmit, Sl, Tyrer, Jp, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, Kb, Dennis, J, Conti, Dv, Casey, G, Gaudet, Mm, Huyghe, Jr, Albanes, D, Aldrich, Mc, Andrew, A, Andrulis, Il, Anton-Culver, H, Antoniou, Ac, Antonenkova, Nn, Arnold, Sm, Aronson, Kj, Arun, Bk, Bandera, Ev, Barkardottir, Rb, Barnes, Dr, Batra, J, Beckmann, Mw, Benitez, J, Benlloch, S, Berchuck, A, Berndt, Si, Bickeböller, H, Bien, Sa, Blomqvist, C, Boccia, Stefania, Bogdanova, Nv, Bojesen, Se, Bolla, Mk, Brauch, H, Brenner, H, Brenton, Jd, Brook, Mn, Brunet, J, Brunnström, H, Buchanan, Dd, Burwinkel, B, Butzow, R, Cadoni, Gabriella, Caldés, T, Caligo, Ma, Campbell, I, Campbell, Pt, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, Al, Chan, At, Chang-Claude, J, Chanock, Sj, Chen, C, Christiani, Dc, Claes, Kbm, Claessens, F, Clements, J, Collée, Jm, Correa, Mc, Couch, Fj, Cox, A, Cunningham, Jm, Cybulski, C, Czene, K, Daly, Mb, Defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, Jl, Dörk, T, Duell, Ej, Dunning, Am, Dwek, M, Eccles, Dm, Edlund, Ck, Edwards, Drv, Ellberg, C, Evans, Dg, Fasching, Pa, Ferris, Rl, Liloglou, T, Figueiredo, Jc, Fletcher, O, Fortner, Rt, Fostira, F, Franceschi, S, Friedman, E, Gallinger, Sj, Ganz, Pa, Garber, J, García-Sáenz, Ja, Gayther, Sa, Giles, Gg, Godwin, Ak, Goldberg, M, Goldgar, De, Goode, El, Goodman, Mt, Goodman, G, Grankvist, K, Greene, Mh, Gronberg, H, Gronwald, J, Guénel, P, Håkansson, N, Hall, P, Hamann, U, Hamdy, Fc, Hamilton, Rj, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Høgdall, E, Hong, Yc, Hopper, Jl, Houlston, R, Hulick, Pj, Hunter, Dj, Huntsman, Dg, Idos, G, Imyanitov, En, Ingles, Sa, Isaacs, C, Jakubowska, A, James, P, Jenkins, Ma, Johansson, M, John, Em, Joshi, Ad, Kaneva, R, Karlan, By, Kelemen, Le, Kühl, T, Khaw, Kt, Khusnutdinova, E, Kibel, A, Kiemeney, La, Kim, J, Kjaer, Sk, Knight, Ja, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, Vn, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, Mt, Lazarus, P, Le, Nd, Lee, E, Lejbkowicz, F, Lenz, Hj, Leslie, G, Lessel, D, Lester, J, Levine, Da, Li, L, Li, Ci, Lindblom, A, Lindor, Nm, Liu, G, Loupakis, F, Lubiński, J, Maehle, L, Maier, C, Mannermaa, A, Marchand, Ll, Margolin, S, May, T, Mcguffog, L, Meindl, A, Middha, P, Miller, A, Milne, Rl, Macinnis, Rj, Modugno, F, Montagna, M, Moreno, V, Moysich, Kb, Mucci, L, Muir, K, Mulligan, Am, Nathanson, Kl, Neal, De, Ness, Ar, Neuhausen, Sl, Nevanlinna, H, Newcomb, Pa, Newcomb, Lf, Nielsen, Fc, Nikitina-Zake, L, Nordestgaard, Bg, Nussbaum, Rl, Offit, K, Olah, E, Olama, Aaa, Olopade, Oi, Olshan, Af, Olsson, H, Osorio, A, Pandha, H, Park, Jy, Pashayan, N, Parsons, Mt, Pejovic, T, Penney, Kl, Peters, Whm, Phelan, Cm, Phipps, Ai, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, Sj, Raskin, L, Rennert, G, Rennert, H, van Rensburg, Ej, Riggan, Mj, Risch, Ha, Risch, A, Roobol, Mj, Rosenstein, B, Rossing, Ma, De Ruyck, K, Saloustros, E, Sandler, Dp, Sawyer, Ej, Schabath, Mb, Schleutker, J, Schmidt, Mk, Setiawan, Vw, Shen, H, Siegel, Em, Sieh, W, Singer, Cf, Slattery, Ml, Sorensen, Kd, Southey, Mc, Spurdle, Ab, Stanford, Jl, Stevens, Vl, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, Aj, Tajara, Eh, Tangen, Cm, Tardon, A, Taylor, Ja, Teare, Md, Teixeira, Mr, Terry, Mb, Terry, Kl, Thibodeau, Sn, Thomassen, M, Bjørge, L, Tischkowitz, M, Toland, Ae, Torres, D, Townsend, Pa, Travis, Rc, Tung, N, Tworoger, S, Ulrich, Cm, Usmani, N, Vachon, Cm, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, Me, Wang, Q, Webb, Pm, Weinberg, Cr, Weinstein, S, Weissler, Mc, Weitzel, Jn, West, Cml, White, E, Whittemore, A, Wichmann, He, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, Ah, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, Kk, Lane, Jm, Saxena, R, Thomas, D, Hung, Rj, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, García-Closas, M, Eeles, Ra, Chenevix-Trench, G, Brennan, Pj, Haiman, Ca, Simard, J, Easton, Df, Gruber, Sb, Pharoah, Pdp, Price, Al, Pasaniuc, B, Amos, Ci, Kraft, P, Lindström, S., Boccia S (ORCID:0000-0002-1864-749X), Cadoni G (ORCID:0000-0001-8244-784X), Jiang, X, Finucane, Hk, Schumacher, Fr, Schmit, Sl, Tyrer, Jp, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, Kb, Dennis, J, Conti, Dv, Casey, G, Gaudet, Mm, Huyghe, Jr, Albanes, D, Aldrich, Mc, Andrew, A, Andrulis, Il, Anton-Culver, H, Antoniou, Ac, Antonenkova, Nn, Arnold, Sm, Aronson, Kj, Arun, Bk, Bandera, Ev, Barkardottir, Rb, Barnes, Dr, Batra, J, Beckmann, Mw, Benitez, J, Benlloch, S, Berchuck, A, Berndt, Si, Bickeböller, H, Bien, Sa, Blomqvist, C, Boccia, Stefania, Bogdanova, Nv, Bojesen, Se, Bolla, Mk, Brauch, H, Brenner, H, Brenton, Jd, Brook, Mn, Brunet, J, Brunnström, H, Buchanan, Dd, Burwinkel, B, Butzow, R, Cadoni, Gabriella, Caldés, T, Caligo, Ma, Campbell, I, Campbell, Pt, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, Al, Chan, At, Chang-Claude, J, Chanock, Sj, Chen, C, Christiani, Dc, Claes, Kbm, Claessens, F, Clements, J, Collée, Jm, Correa, Mc, Couch, Fj, Cox, A, Cunningham, Jm, Cybulski, C, Czene, K, Daly, Mb, Defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, Jl, Dörk, T, Duell, Ej, Dunning, Am, Dwek, M, Eccles, Dm, Edlund, Ck, Edwards, Drv, Ellberg, C, Evans, Dg, Fasching, Pa, Ferris, Rl, Liloglou, T, Figueiredo, Jc, Fletcher, O, Fortner, Rt, Fostira, F, Franceschi, S, Friedman, E, Gallinger, Sj, Ganz, Pa, Garber, J, García-Sáenz, Ja, Gayther, Sa, Giles, Gg, Godwin, Ak, Goldberg, M, Goldgar, De, Goode, El, Goodman, Mt, Goodman, G, Grankvist, K, Greene, Mh, Gronberg, H, Gronwald, J, Guénel, P, Håkansson, N, Hall, P, Hamann, U, Hamdy, Fc, Hamilton, Rj, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Høgdall, E, Hong, Yc, Hopper, Jl, Houlston, R, Hulick, Pj, Hunter, Dj, Huntsman, Dg, Idos, G, Imyanitov, En, Ingles, Sa, Isaacs, C, Jakubowska, A, James, P, Jenkins, Ma, Johansson, M, John, Em, Joshi, Ad, Kaneva, R, Karlan, By, Kelemen, Le, Kühl, T, Khaw, Kt, Khusnutdinova, E, Kibel, A, Kiemeney, La, Kim, J, Kjaer, Sk, Knight, Ja, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, Vn, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, Mt, Lazarus, P, Le, Nd, Lee, E, Lejbkowicz, F, Lenz, Hj, Leslie, G, Lessel, D, Lester, J, Levine, Da, Li, L, Li, Ci, Lindblom, A, Lindor, Nm, Liu, G, Loupakis, F, Lubiński, J, Maehle, L, Maier, C, Mannermaa, A, Marchand, Ll, Margolin, S, May, T, Mcguffog, L, Meindl, A, Middha, P, Miller, A, Milne, Rl, Macinnis, Rj, Modugno, F, Montagna, M, Moreno, V, Moysich, Kb, Mucci, L, Muir, K, Mulligan, Am, Nathanson, Kl, Neal, De, Ness, Ar, Neuhausen, Sl, Nevanlinna, H, Newcomb, Pa, Newcomb, Lf, Nielsen, Fc, Nikitina-Zake, L, Nordestgaard, Bg, Nussbaum, Rl, Offit, K, Olah, E, Olama, Aaa, Olopade, Oi, Olshan, Af, Olsson, H, Osorio, A, Pandha, H, Park, Jy, Pashayan, N, Parsons, Mt, Pejovic, T, Penney, Kl, Peters, Whm, Phelan, Cm, Phipps, Ai, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, Sj, Raskin, L, Rennert, G, Rennert, H, van Rensburg, Ej, Riggan, Mj, Risch, Ha, Risch, A, Roobol, Mj, Rosenstein, B, Rossing, Ma, De Ruyck, K, Saloustros, E, Sandler, Dp, Sawyer, Ej, Schabath, Mb, Schleutker, J, Schmidt, Mk, Setiawan, Vw, Shen, H, Siegel, Em, Sieh, W, Singer, Cf, Slattery, Ml, Sorensen, Kd, Southey, Mc, Spurdle, Ab, Stanford, Jl, Stevens, Vl, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, Aj, Tajara, Eh, Tangen, Cm, Tardon, A, Taylor, Ja, Teare, Md, Teixeira, Mr, Terry, Mb, Terry, Kl, Thibodeau, Sn, Thomassen, M, Bjørge, L, Tischkowitz, M, Toland, Ae, Torres, D, Townsend, Pa, Travis, Rc, Tung, N, Tworoger, S, Ulrich, Cm, Usmani, N, Vachon, Cm, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, Me, Wang, Q, Webb, Pm, Weinberg, Cr, Weinstein, S, Weissler, Mc, Weitzel, Jn, West, Cml, White, E, Whittemore, A, Wichmann, He, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, Ah, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, Kk, Lane, Jm, Saxena, R, Thomas, D, Hung, Rj, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, García-Closas, M, Eeles, Ra, Chenevix-Trench, G, Brennan, Pj, Haiman, Ca, Simard, J, Easton, Df, Gruber, Sb, Pharoah, Pdp, Price, Al, Pasaniuc, B, Amos, Ci, Kraft, P, Lindström, S., Boccia S (ORCID:0000-0002-1864-749X), and Cadoni G (ORCID:0000-0001-8244-784X)

Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019

33. Asparaginase-like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study

Author

Fonnes, T, primary, Trovik, J, additional, Edqvist, P-HD, additional, Fasmer, KE, additional, Marcickiewicz, J, additional, Tingulstad, S, additional, Staff, AC, additional, Bjørge, L, additional, Amant, F, additional, Haldorsen, IS, additional, Werner, HMJ, additional, Akslen, LA, additional, Tangen, IL, additional, and Krakstad, C, additional

Published
2018
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35. Epigenome-based cancer risk prediction: Rationale, opportunities and challenges

Author

Widschwendter, M, Jones, A, Evans, I, Reisel, D, Dillner, J, Sundström, K, Steyerberg, E, Vergouwe, Y, Wegwarth, O, Rebitschek, F, Siebert, U, Sroczynski, G, De Beaufort, I, Bolt, I, Cibula, D, Zikan, M, Bjørge, L, Colombo, N, Harbeck, N, Dudbridge, F, Tasse, A, Knoppers, B, Joly, Y, Teschendorff, A, Pashayan, N, Widschwendter, Martin, Jones, Allison, Evans, Iona, Reisel, Daniel, Dillner, Joakim, Sundström, Karin, Steyerberg, Ewout W., Vergouwe, Yvonne, Wegwarth, Odette, Rebitschek, Felix G., Siebert, Uwe, Sroczynski, Gaby, De Beaufort, Inez D., Bolt, Ineke, Cibula, David, Zikan, Michal, Bjørge, Line, Colombo, Nicoletta, Harbeck, Nadia, Dudbridge, Frank, Tasse, Anne-Marie, Knoppers, Bartha M., Joly, Yann, Teschendorff, Andrew E., Pashayan, Nora, Widschwendter, M, Jones, A, Evans, I, Reisel, D, Dillner, J, Sundström, K, Steyerberg, E, Vergouwe, Y, Wegwarth, O, Rebitschek, F, Siebert, U, Sroczynski, G, De Beaufort, I, Bolt, I, Cibula, D, Zikan, M, Bjørge, L, Colombo, N, Harbeck, N, Dudbridge, F, Tasse, A, Knoppers, B, Joly, Y, Teschendorff, A, Pashayan, N, Widschwendter, Martin, Jones, Allison, Evans, Iona, Reisel, Daniel, Dillner, Joakim, Sundström, Karin, Steyerberg, Ewout W., Vergouwe, Yvonne, Wegwarth, Odette, Rebitschek, Felix G., Siebert, Uwe, Sroczynski, Gaby, De Beaufort, Inez D., Bolt, Ineke, Cibula, David, Zikan, Michal, Bjørge, Line, Colombo, Nicoletta, Harbeck, Nadia, Dudbridge, Frank, Tasse, Anne-Marie, Knoppers, Bartha M., Joly, Yann, Teschendorff, Andrew E., and Pashayan, Nora

Abstract

The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.

Published
2018

36. A phase 1 study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the recommended phase 2 dose (RP2D) in women with platinum-sensitive epithelial ovarian cancer (ENGOT-OV24/AVANOVA1)

Author

Mirza, M.R., primary, Wang, J., additional, Mau-Sørensen, M., additional, Birrer, M.J., additional, Wang, X., additional, Jørgensen, M., additional, Zhang, Z-Y., additional, Roed, H., additional, Malander, S., additional, Nielsen, F., additional, Bjørge, L., additional, Lassen, U., additional, Boufercha, L., additional, Brøsen, K., additional, Kansra, V., additional, and Mäenpää, J., additional

Published
2017
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37. Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

Author

Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, Baker, H, Bandera, EV, Bean, YT, Beckmann, MW, Berchuck, A, Bisogna, M, Bjørge, L, Bogdanova, N, Brinton, L, Brooks-Wilson, A, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, D, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, CK, Hosono, S, Iversen, ES, Jakubowska, A, Paul, J, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, J, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, and Liang, D

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

© 2015 American Association for Cancer Research. Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Published
2015
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38. The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia

Author

Thomsen, L., Mccarthy, N., Melton, P., Cadby, G., Austgulen, R., Nygård, O., Johnson, M., Brennecke, S., Moses, Eric, Bjørge, L., Iversen, A., Thomsen, L., Mccarthy, N., Melton, P., Cadby, G., Austgulen, R., Nygård, O., Johnson, M., Brennecke, S., Moses, Eric, Bjørge, L., and Iversen, A.

Abstract

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. OBJECTIVE: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS:: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n?=?1006) and nonpreeclamptic controls (n?=?816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS:: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P?=?0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency?=?0.15). CONCLUSION:: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on pree

Published
2016

39. Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort

Author

Thomsen, L., Melton, P., Tollaksen, K., Lyslo, I., Roten, L., Odland, M., Strand, K., Nygard, O., Sun, C., Iversen, A., Austgulen, R., Moses, Eric, Bjørge, L., Thomsen, L., Melton, P., Tollaksen, K., Lyslo, I., Roten, L., Odland, M., Strand, K., Nygard, O., Sun, C., Iversen, A., Austgulen, R., Moses, Eric, and Bjørge, L.

Abstract

Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. Methods: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. Results: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r)=0.60)] and severity (H2r=0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r=0.25). Other heritable phenotypes identified included SGA (H2r=0.40), chronic hypertension (H2r=0.57), severity of atherothrombotic cardiovascular disease (H2r=0.31), BMI (H2r=0.60) and pulmonary disease (H2r=0.91). The heritable phenotype preeclampsia overlapped with SGA (P=0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P<0.01), SGA (P=0.02) and BMI (P=0.02). Conclusion: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits.

Published
2015

40. 953P - A phase 1 study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the recommended phase 2 dose (RP2D) in women with platinum-sensitive epithelial ovarian cancer (ENGOT-OV24/AVANOVA1)

Author

Mirza, M.R., Wang, J., Mau-Sørensen, M., Birrer, M.J., Wang, X., Jørgensen, M., Zhang, Z-Y., Roed, H., Malander, S., Nielsen, F., Bjørge, L., Lassen, U., Boufercha, L., Brøsen, K., Kansra, V., and Mäenpää, J.

Published
2017
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41. Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

Author

Johansson, A., Curran, J., Johnson, M., Freed, K., Fenstad, M., Bjørge, L., Eide, I., Carless, M., Rainwater, D., Goring, H., Austgulen, R., Moses, Eric, Blangero, J., Johansson, A., Curran, J., Johnson, M., Freed, K., Fenstad, M., Bjørge, L., Eide, I., Carless, M., Rainwater, D., Goring, H., Austgulen, R., Moses, Eric, and Blangero, J.

Abstract

Preeclampsia (PE) is a serious complication of pregnancy, which is highly correlated with later life cardiovascular disease (CVD). Many risk factors are common for both diseases, but the contribution of shared genes remains to be determined. In this study, we used an integrative strategy to assess lipid traits as risk factors for PE and CVD by whole genome transcriptional profiling performed on Norwegian decidua basalis tissues (N=95) from preeclamptic and normal pregnancies and on blood lymphocytes (N=1240) from the San Antonio Family Heart Study (SAFHS). Among 222 genes that were differentially expressed (false discovery rate (FDR) P-value <0.05) between the PE, cases and controls, we found one gene, ACOX2 (acyl-coenzyme A oxidase 2, branched chain), that was downregulated in PE whose transcription was also inversely correlated with triglyceride levels (P=5.6 × 10−7; FDR P-value=0.0002) in SAFHS. We further report associations between SNPs in the ACOX2 gene and the transcription level (P-value=0.0045) of the gene, as well as with triglyceride levels (P-value=0.0051). ACOX2 is involved in bile acid production, a process that has been associated with both oxidative stress and regulation of triglyceride levels. Oxidative stress and increased triglyceride levels are known risk factors for CVD and both have also been associated with PE. Our results suggest that downregulation of ACOX2 is a shared risk factor for PE and CVD.

Published
2011

42. Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without pre-eclampsia

Author

Lian, I., Løset, M., Mundal, S., Fenstad, M., Johnson, M., Eide, I., Bjørge, L., Freed, K., Moses, Eric, Austgulen, R., Lian, I., Løset, M., Mundal, S., Fenstad, M., Johnson, M., Eide, I., Bjørge, L., Freed, K., Moses, Eric, and Austgulen, R.

Abstract

Objectives: Endoplasmic reticulum (ER) stress has been implicated in both pre-eclampsia (PE) and fetal growth restriction (FGR), and is characterised by activation of three signalling branches: 1) PERK-pEIF2a, 2) ATF6 and 3) splicing of XBP1(U) into XBP1(S). To evaluate the contribution of ER stress in the pathogenesis of PE relative to FGR, we compared levels of ER stress markers in decidual tissue from pregnancies complicated by PE and/or FGR. Study design: Whole-genome transcriptional profiling was performed on decidual tissue from women with PE (n = 13), FGR (n = 9), PE+FGR (n = 24) and controls (n = 58), and used for pathway and targeted transcriptional analyses of ER stress markers. The expression and cellular localisation of ER stress markers was assesses by Western blot and immunofluorescence analyses. Results: Increased ER stress was observed in FGR and PE+FGR, including both the PERK-pEIF2a and ATF6 signalling branches, whereas ER stress was less evident in isolated PE. However, these cases demonstrated elevated levels of XBP1(U) protein. ATF6 and XBP1 immunoreactivity was detected in most (>80%) extravillous trophoblasts, decidual cells and macrophages. No difference in the proportion of immunopositive cells or staining pattern was observed between study groups. Conclusions: Increased PERK-pEIF2a and ATF6 signalling have been associated with decreased cellular proliferation and may contribute to the impaired placental growth characterising pregnancies with FGR and PE+FGR. XBP1(U) has been proposed as a negative regulator of ER stress, and increased levels in PE may reflect a protective mechanism against the detrimental effects of ER stress.

Published
2011

43. A transcriptional profile of the decidua in preeclampsia

Author

Løset, M., Mundal, S., Johnson, M., Fenstad, M., Freed, K., Lian, I., Eide, I., Bjørge, L., Blangero, J., Moses, Eric, Austgulen, R., Løset, M., Mundal, S., Johnson, M., Fenstad, M., Freed, K., Lian, I., Eide, I., Bjørge, L., Blangero, J., Moses, Eric, and Austgulen, R.

Abstract

OBJECTIVE: We sought to obtain insight into possible mechanisms underlying preeclampsia using genomewide transcriptional profiling in decidua basalis. STUDY DESIGN: Genomewide transcriptional profiling was performed on decidua basalis tissue from preeclamptic (n = 37) and normal (n = 58) pregnancies. Differentially expressed genes were identified and merged into canonical pathways and networks. RESULTS: Of the 26,504 expressed transcripts detected, 455 were differentially expressed (P < .05; false discovery rate, P < .1). Both novel (ARL5B, SLITRK4) and previously reported preeclampsia-associated (PLA2G7, HMOX1) genes were identified. Pathway analysis revealed that tryptophan metabolism, endoplasmic reticulum stress, linoleic acid metabolism, notch signaling, fatty acid metabolism, arachidonic acid metabolism, and NRF2-mediated oxidative stress response were overrepresented canonical pathways. CONCLUSION: In the present study single genes, canonical pathways, and gene-gene networks that are likely to play an important role in the pathogenesis of preeclampsia have been identified. Future functional studies are needed to accomplish a greater understanding of the mechanisms involved.

Published
2011

44. STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women : data from the Second Nord-Trondelag Health Study

Author

Fenstad, M H, Johnson, M P, Løset, M, Mundal, S B, Roten, L T, Eide, I P, Bjørge, L, Sande, R K, Johansson, Åsa, Dyer, T D, Forsmo, S, Blangero, J, Moses, E K, Austgulen, R, Fenstad, M H, Johnson, M P, Løset, M, Mundal, S B, Roten, L T, Eide, I P, Bjørge, L, Sande, R K, Johansson, Åsa, Dyer, T D, Forsmo, S, Blangero, J, Moses, E K, and Austgulen, R

Abstract

Variation in the Storkhead box-1 (STOX1) gene has previously been associated with pre-eclampsia. In this study, we assess candidate single nucleotide polymorphisms (SNPs) in STOX1 in an independent population cohort of pre-eclamptic (n = 1.139) and non-pre-eclamptic (n = 2.269) women (the HUNT2 study). We also compare gene expression levels of STOX1 and its paralogue, Storkhead box-2 (STOX2) in decidual tissue from pregnancies complicated by pre-eclampsia and/or fetal growth restriction (FGR) (n = 40) to expression levels in decidual tissue from uncomplicated pregnancies (n = 59). We cannot confirm association of the candidate SNPs to pre-eclampsia (P > 0.05). For STOX1, no differential gene expression was observed in any of the case groups, whereas STOX2 showed significantly lower expression in deciduas from pregnancies complicated by both pre-eclampsia and FGR as compared with controls (P = 0.01). We further report a strong correlation between transcriptional alterations reported previously in choriocarcinoma cells over expressing STOX1A and alterations observed in decidual tissue of pre-eclamptic women with FGR.

Published
2010
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45. STOX2 but not STOX1 is differentially expressed in decidua from preeclamptic women: Data from the Second Nord-Trøndelag Health Study

Author

Fenstad, M., Johnson, M., Løset, M., Mundal, S., Roten, L., Eide, I., Bjørge, L., Sande, R., Johansson, A., Dyer, T., Forsmo, S., Blangero, J., Moses, Eric, Austgulen, R., Fenstad, M., Johnson, M., Løset, M., Mundal, S., Roten, L., Eide, I., Bjørge, L., Sande, R., Johansson, A., Dyer, T., Forsmo, S., Blangero, J., Moses, Eric, and Austgulen, R.

Abstract

Variation in the Storkhead box-1 (STOX1) gene has previously been associated with pre-eclampsia. In this study, we assess candidate single nucleotide polymorphisms (SNPs) in STOX1 in an independent population cohort of pre-eclamptic (n = 1.139) and non-pre-eclamptic (n = 2.269) women (the HUNT2 study). We also compare gene expression levels of STOX1 and its paralogue, Storkhead box-2 (STOX2) in decidual tissue from pregnancies complicated by pre-eclampsia and/or fetal growth restriction (FGR) (n = 40) to expression levels in decidual tissue from uncomplicated pregnancies (n = 59). We cannot confirm association of the candidate SNPs to pre-eclampsia (P > 0.05). For STOX1, no differential gene expression was observed in any of the case groups, whereas STOX2 showed significantly lower expression in deciduas from pregnancies complicated by both pre-eclampsia and FGR as compared with controls (P = 0.01). We further report a strong correlation between transcriptional alterations reported previously in choriocarcinoma cells over expressing STOX1A and alterations observed in decidual tissue of pre-eclamptic women with FGR. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Published
2010

47. Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas

Author

Haldorsen, I S, primary, Stefansson, I, additional, Grüner, R, additional, Husby, J A, additional, Magnussen, I J, additional, Werner, H M J, additional, Salvesen, Ø O, additional, Bjørge, L, additional, Trovik, J, additional, Taxt, T, additional, Akslen, L A, additional, and Salvesen, H B, additional

Published
2013
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48. Ascitic complement system in ovarian cancer.

Author

Bjørge, L, Hakulinen, J, Vintermyr, O K, Jarva, H, Jensen, T S, Iversen, O E, Meri, S, and Bjørge, L

Subjects
*OVARIAN cancer, *CANCER patients, *COMPLEMENT (Immunology), *BLOOD proteins, *MOLECULAR immunology, *ANTIGENS
Abstract

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised. [ABSTRACT FROM AUTHOR]

Published
2005
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49. P54 Classification of pre-eclamptic pregnancies in health registries

Author

Vestrheim, L.C., primary, Austgulen, R., additional, Melve, K.K., additional, Roten, L.T., additional, Tappert, C., additional, Araya, E., additional, Tollaksen, K., additional, Bærheim, G., additional, Leuchsner, H., additional, Fenstad, M.H., additional, Mascali, F., additional, and Bjørge, L., additional

Published
2010
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