1,721,633 research outputs found
ZuptEC: Phase III study or zuptarelin doxorubicin (AEZS-108) te platinum-taxane pretreated endontetrial cancer (Study AEZS-108-050)
No full textZuptEC: Phase III study or zuptarelin doxorubicin (AEZS-108) te platinum-taxane pretreated endontetrial cancer (Study AEZS-108-050)
No full textKan Preventie van Mesotheelschade tijdens Endoscopische Chirurgie Adhesievorming en Tumorimplantatie Verminderen ?
No full textLaparoscopic surgery advanced over the last years as it holds the promise of reduced invasiveness and thus of reduced adhesion formation. Results on reduced adhesion formation were however not as good as expected and new approaches to prevent the deleterious complications such as bowel obstruction, infertility and chronic pelvic pain were investigated.Over the last years we developed a laparoscopic mouse model on which preventive measurements concerning gas (temperature, humidification, oxygen) and other means (i.e. dexamethasone, barriers) were tested and the most promising were selected. These favorable actions needed to be brought into clinical practice to reduce adhesion formation and to bring laparoscopic surgery to a new standard.Tumor implantation reduced with the addition of 3% of oxygen to the CO2 pneumoperitoneum in our laparoscopic mouse model. There was however no clinical correlation with reduced port site metastases by adding 4% of oxygen to the CO2 pneumoperitoneum in women undergoing laparoscopy for ovarian malignancies.Intraperitoneal injection of cultured mesothelial cells did decrease adhesion formation in a dose-response dependable way. To bring this approach to clinical practice will need the development of other means to safely remove, culture and inject mesothelial cells in humans in the peri-operative phase.The direct beneficial effect on the peritoneum of the addition of oxygen to the CO2 pneumoperitoneum was demonstrated in mice with scanning electron microscopy, but these experiments were not reproducible in humans. Indirect ways to measure the influence of the addition of oxygen to the CO2 pneumoperitoneum were investigated.Absorption of CO2 was investigated by the study of end tidal CO2 (ET CO2) where we noticed a significant decrease when 4% oxygen was added to the CO2 pneumoperitoneum. Perhaps related to this, was the significant decrease in post-operative pain and inflammation in women who received the oxygenated gas.From ongoing mice experiments we learned that full conditioning of the peritoneal cavity with humidification of the gas at 32°C and with addition 4% of oxygen and 10% of nitrous oxide further reduced adhesion formation.Clinical experiments with full conditioning of the peritoneal cavity studying ET CO2, pain, inflammation and fluid resorption as we carried out with the addition of 4% of oxygen all showed a beneficial effect, with even some more pronounced results on pain and inflammation.To preserve the integrity of the mesothelial layer, injection of cultured mesothelial cells or altering the insufflation gas did provide evidence, but also extensive lavage of the peritoneal cavity did improve inflammatory parameters, suggesting a depletion of inflammatory cells able to degrade the surgical lesion.The peritoneum is a delicate organ which is influenced by its environment in a direct way. Homeostasis of the environment is essential to decrease adhesion formation, post-operative pain and to minimize anesthesiologic problems.Preserving is better than restoring and with this new way of looking at, and entering the peritoneal cavity, laparoscopic surgery may step into a new era.status: Publishe
Epitheliaal ovarium carcinoma: moleculaire en klinische predictoren voor platinum resistentie
No full textMost patients with ovarian cancer are still diagnosed in advanced stage disease needing intensive therapy with debulking surgery and chemotherapy. However, 25 % of patients will progress during or will relapse within 6 months of the primary therapy. These patients are called the platinum resistant patients. Unfortunately there are not many therapeutic options for this group of patients available. This doctoral thesis was performed in an effort to identify platinum resistant patients at diagnosis by searching for molecular and clinical predictors for platinum resistance. In this way the burden of a cytotoxic therapy compromising bone marrow reserve and quality of life could be avoided and targets for more individualised therapy could be found. Proteins represent the actual functional molecules in a cell and when a mutation occurs at the DNA level, it is the protein that ultimately will be affected. Therefore the study of the proteome, meaning the entire protein content produced by a cell during its life cycle, can help us to detect changes occurring during a particular disease process. Challenges in proteomic studies in blood are the presence of high abundant proteins masking the detection of the low concentrated ones, inter- and intra-individual differences and the need for prospectively and well controlled collected samples. Therefore we took part in a European consortium, the OVCAD study, where biological samples of ovarian cancer patients were prospectively collected according to a strict protocol. In this way we were able to collect a substantial number of samples in a relative short study period. In an attempt to minimise variation in protein content and to improve the probability of finding an ovarian cancer specific marker we decided to perform proteomic analysis on tumor tissue biopsies. Moreover, as ovarian tumor tissue biopsies consist of a heterogeneous amount of cells, we preferred to work with laser microdissected ovarian cancer cells. In the molecular part of this thesis, we firstly identified current problems and obstacles in proteomic studies and subsequently defined a protocol to combine laser microdissection and SELDI-TOF MS analysis in ovarian cancer tissue to achieve robust protein profiles. We demonstrated that changes in sample handling have influences on the protein profile and that strict protocols are necessary to obtain reliable results.Using this protocol we performed a first analysis on LMD ovarian tumor tissue of platinum sensitive vs. resistant patients. Based on the obtained profiles we determined that CM10 and IMAC30 were the ProteinChip surfaces of interest to be used further SELDI-TOF MS analysis.This model was then applied on the prospectively collected OVCAD samples and a prediction model was build to classify patients according to platinum sensitivity. Furthermore, we were able to confirm differentially expressed peaks in the lower molecular mass range between platinum resistant and sensitive patients. One of the upregulated peaks in patients with platinum sensitive disease with an m/z value of 2885 Da, could be identified as Histone H2B type 1-D (H2B1D_Human). Histone modification is currently used in other cancers as target for therapy and this finding could therefore have a clinical impact and warrants further investigation. Subsequently a validation study was performed but was not able to confirm the results of the training set. We believe other techniques such as immunohistochemistry should be considered to establish the role of Histone H2B type 1-D in the predictions of platinum resistance in ovarian cancer. In the clinical part of this dissertation, we assessed the clinical data of patients included in the OVCAD study in relation to their platinum free interval to determine clinical predictors for response. After multivariate analysis we identified the presence of peritoneal carcinomatosis, high levels of CA125 at the end of therapy and the achievement of complete remission at the end of primary therapy as the most significant factors for platinum resistance. These data could guide us in the follow-up of EOC patients who are at risk for early relapse.In a next chapter we evaluated the effect of a dose dense or weekly paclitaxel carboplatinum regimen for recurrent ovarian cancer in an attempt to overcome platinum resistance. Both regimens achieved good RR of 37% in the platinum resistant group. Toxicity varied between both schemes but was acceptable. In conclusion the molecular studies in this thesis need further investigation and might have a clinical impact in the search for targeted therapy in resistant epithelial ovarian cancer. Secondly, in the clinical part we identified patients at risk for early recurrence and we suggest that even in platinum resistant patients a rechallenge with a modified paclitaxel and platinum containing regimen is a valuable treatment option.status: Publishe
De rol van genetische veranderingen in de behandeling van het ovarium carcinoom
No full textOvarian cancer has the highest mortality of all gynaecologic malignancies in the developed world. Following the standard first-line treatment of cytoreductive surgery and platinum-based chemotherapy, there are large inter-individual differences in therapy-related toxicities and outcome. Most patients benefit from initial treatment, but progressively develop platinum resistance during subsequent lines. Advanced genetic technologies have recently improved our understanding of the genetic landscape, characterizing the different clinical phenotypes. However, few predictive or prognostic biomarkers have been identified and consequently less therapeutic stratification has been introduced. In view of the persistent need for a more effective targeted approach for this poor prognostic disease, we aimed to further decipher underlying genetic markers that potentially could tailor therapeutic strategies.
Reviewing the current knowledge on the genetic characteristics underlying the most frequent high grade serous (HGSOC) subtype (chapter 3), we remarked the striking heterogeneity with few recurrent mutations and a high number of copy number alterations causing genomic instability.
We undertook a first study (chapter 4) to identify germline variants in genes involved in platinum metabolism (ABCB1/MDR1, ABCC1, ABCA1, CYP3A4, GSTP1 and ERCC2) that may determine side-effects and resistance following platinum-based therapy. However, independent validation of these associations is needed prior to their potential clinical application. We contributed this study to the international Ovarian Cancer Association Consortium (OCAC) evaluating associations between outcome and candidate polymorphisms in a maximally powered population, but these studies failed to confirm previously reported associations.
To understand the clonal evolution of genetic characteristics towards platinum resistance, we applied in a next step (chapter 5) whole-exome sequencing, targeted resequencing and SNP array profiling to paired samples from diagnosis and recurrence. As such, we identified branched clonal evolutionary patterns causing a considerable degree of heterogeneity between these temporally divided biopsies. This advocates the need for taking biopsies at each recurrence, to optimize clinical trial design when testing targeting therapies. Deficiency of the homologous recombination pathway (HRD) characterized the recurrence biopsies at least to the same extend as the primary biopsies, both for resistant as for sensitive recurrences, concluding that previously described secondary events restoring HRD function are not the major mechanism driving platinum resistance. These findings suggest the potential efficacy of PARP (poly-ADP ribose polymerase) inhibitors for platinum-resistant relapses. While we failed to detect recurrence-specific or resistance-specific aberrations, a ‘platinum score’ of 13 somatic copy number alterations (SCNAs) was developed. This score includes focal amplifications among interesting cancer genes such as CCNE1, ERBB2 and TERT, and correlated with the platinum-free interval (PFI) following the time point the biopsy was taken. An increase of this score in recurrent tumors predicted the change in PFI during subsequent therapy, indicating that a gradual increase in accumulating CNAs during treatment renders the tumor more oncogenic. This way, the adaptability of the HGSOC genome provides the molecular basis of treatment resistance. To improve therapeutic outcomes, a combined approach targeting the different mechanisms included in the ‘platinum score’ might be the step forward.
In the future our research group will further focus on the validation of the identified genetic hallmarks of resistance, both for platinum and PARP inhibitors. The application of less invasive technologies such as ‘liquid biopsies’ containing circulating tumor-DNA, might bypass the need for large collections of fresh frozen relapse-biopsies, that limited the current research in validating low prevalent mechanisms as potential drivers of therapy response.status: Publishe
Rol van genomische veranderingen als prognostische en predictieve factoren in het epitheliaal ovariumcarcinoom
No full textMost patients with epithelial ovarian cancer (EOC) are still diagnosed in advanced stage disease, needing extensive debulking surgery and (neo)adjuvant platinum-based chemotherapy. Although initial response rates are good, most patients progressively develop platinum resistance during subsequent lines. EOC is a very heterogeneous disease, with different subtypes with distinct behavior and individually different responses to chemotherapy, even within the same histology. However, this heterogeneity is not reflected in the treatment, where the different subtypes are still treated as a single disease entity. The challenge for further optimization of treatment is thus to overcome resistance to platinum-based chemotherapy and to offer a more tailored therapy to the different subtypes. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The aim of this thesis was to identify novel and validate some previously investigated genomic alterations in EOC and to search for the genomic alterations behind the differential chemotherapy response.
In chapter 3, a current perspective on the genomic alterations of EOC is given, reviewing the most important studies regarding somatic mutations, copy number alterations, microRNAs, gene expression and DNA methylation in EOC.
In a first study (chapter 4.1), 262 primary EOCs of mixed histology were genotyped for more than 100 hotspot mutations in genes potentially acting as prognostic markers in EOC. The main finding was that somatic mutations are limited to the, so-called, Type I tumors (low-grade serous, mucinous, endometrioid and clear cell), which generally respond worse to standard platinum-based chemotherapy. Of these, 49% were KRAS or PIK3CA mutant (versus 2.9% in the Type II tumors). Each histological subtype seemed to be characterized by distinct somatic mutations. PIK3CA mutations were predominantly found in clear cell and endometrioid carcinomas whereas mucinous subtypes harbored significantly more KRAS mutations. Within the serous histotype, low-grade tumors were more frequently KRAS or BRAF mutated than high-grade tumors. None of the mutations had a prognostic or predictive role. We concluded that the EOC histotypes, referred to as Type I, should not be regarded as one group but as distinct disease entities as they all have different driver mutations. We suggest that these tumors should not be treated with conventional chemotherapy but with targeted therapies based on their driver mutations.
Secondly, we assessed somatic copy number alterations in a discovery (n = 86) and validation cohort (n = 115) of EOCs using high-resolution SNP arrays (chapter 4.2). We identified 53 regions to be significantly overrepresented in EOC, of which 6 correlated with overall survival (OS), progression-free survival (PFS) or platinum-free interval (PFI) in the discovery cohort. In the validation cohort, amplifications of the chromosomal region 14q32.33 also correlated with OS. Amplifications of 14q32.33 were also assessed in a pooled analysis involving both cohorts and published SCNA data from the Cancer Genome Atlas (n = 227). In this pooled analysis of 428 tumors, 14q32.33 amplifications significantly reduced OS, PFS and PFI. This region contains AKT1 as a potential driver gene, a gene which previously has been implicated as a key mediator of platinum resistance in cancer cell lines and mouse models. Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region. These findings suggest that patients carrying 14q32.33 amplifications should benefit from a different therapy in first-line setting and could be offered treatment with an AKT-inhibitor.
In a third study (chapter 4.3), a cohort of 100 advanced stage (FIGO IIb – IV) serous EOCs was analyzed for 13 microRNAs, selected from the literature based on their association with ovarian cancer. We confirmed the prognostic role of the miR-200 and let-7 family. In addition, we sought to identify microRNAs associated with differential chemotherapy response and OS via an unbiased genome-wide miRNA screen (n = 38). Unfortunately, none of the 25 selected miRNAs from the discovery cohort, could be confirmed in the independent validation set of 62 EOCs. However, a trend was seen for miR-193b in relation to PFI, but our numbers were too small to draw firm conclusions.
In the search for new targeted therapies to improve survival in EOC, the epidermal growth factor receptor (EGFR) has been considered a promising target. In a last part of this thesis, we evaluated in a randomized phase III study the efficacy of erlotinib, an EGFR tyrosine kinase inhibitor, as maintenance therapy after first-line chemotherapy (chapter 5.1). Unfortunately, this strategy did not improve PFS or OS. We searched for biomarkers to predict which patients would benefit from this treatment (chapter 5.2). No subgroup could be identified with improved effect of erlotinib, based on immunohistochemistry or FISH for EGFR, or mutations in genes related to the EGFR pathway. However, patients with a positive FISH EGFR status had a worse OS (46.1 months versus 67.0 months) and PFS (9.6 months versus 16.1 months) than those with a negative status, making it an attractive molecular biomarker for further investigation as a criterion for selecting patients for prospective studies on erlotinib or other anti-EGFR therapies in EOC.
Overall, specific genomic alterations associated with differential therapy response and patient outcome were identified in this thesis. It is clear that individualized and targeted therapy, based on the molecular drivers in the tumor, is proposed to be the future treatment strategy of ovarian cancer patients. The discovery of predictive biomarkers that identify patients which benefit from these targeted therapies is paramount to the success of these treatments.status: Publishe
BRCA mutaties in de Belgische bevolking
No full textSummary BRCA1/2 mutations are the most commonlyidentified germ line gene mutations in patients with hereditary breast and ovarian cancer (HBOC). The BRCA genes have plethora of critical cellular functions, including repair of DNA double-strand breaks, explainingthe susceptibility for tumor development at young age and clustered in families seen the autosomal dominant inheritance. Over the years, knowledge about these genes and their function is steadily growing. Integration of this information in daily clinical practice permits a better follow-up of this group of patients. However, still many questions remain unresolved and continuing research in this topic remains compulsory. In this doctoral thesis, based on a database of nearly 1800 patients (982 HBOC families) tested at the University Hospital Leuven, we tried to get more insight in some topics with clinical relevance in this wide field concerning BRCA related tumors. Because of the broad population specific mutation spectrum of these genes, we were interested in the mutations identified at our center. We were able to list the most frequently present mutations and demonstrated that some of them were quite specific for our Belgian population andpotentially founder mutations. Moreover, collecting all clinical available data of these tested patients, permitted to look for the pathologic features of these tumors and their clinical presentation. The data made us believe in a certain genotype/phenotype correlation. If confirmed in larger studies, this can help us in the future in better counseling our patients. Collection of breast and ovarian tissue retrieved at preventive surgery offered the opportunity to perform further investigations of precursor lesions. This precursor lesions can learn us a lot about the pathogenesis and behavior of the tumors, which could be reflected than again to our clinical practice. Besides collection of preventively removed specimens, availability of tumor samples from these BRCA patients also permits histologic and molecular analysis. Indeed, performing array analysis from sporadic andBRCA1 related ovarian cancer tissues, allowed us to investigate and compare the pathways involved in the pathogenesis of these tumors. Thosepathways are the cornerstone in the development of new (target) therapies and can help in the decision on treatment strategies in function of the presence/absence of a BRCA mutation. In conclusion, in this doctoral thesis we investigated on BRCA related tumors at 3 different levels. Firstly we aimed to describe the mutations presenting in our population and correlated clinical data to these genetic information. In a second part we evaluated preventive strategiesand presence of precursor lesions in order to optimize our counseling and treatment options. In the last part, a molecular study was performed aiming the identification of distinct pathways in these BRCA related tumors compared to the sporadic ones. These 3 parts howevermerge into one another and all contributed to a better counseling, preventive and therapeutic approach of our BRCA related patients in daily clinical practice.status: Publishe
De evaluatie van nieuwe biomerkers in Gynaecologische Tumoren. De opkomende rol van Proteomics
No full textThe objective of this research project was to validate newly discovered biomarkers and to discover new biomarkers by using proteomics in serum or plasma of ovarian and cervical tumours.The first diagnostic problem was the differentiation between a benign and a malignant ovarian mass. Even when a pelvic mass is present, it is difficult to discriminate between benign and malignant disease. In a first study the ROMA algorithm, a combination of CA125 and HE4, was validated and compared to the gold standard CA125. In this large study we were able to demonstrate that neither HE4, nor the ROMA increased the detection of malignant disease.However, the differentiation of benign and malignant masses is not purely based on tumour markers alone. This is why a second study was performed, in which the diagnostic accuracy of ROMA was assessed and compared to the two most widely used ultrasound methods, the risk of malignancy index (RMI) and subjective assessment by ultrasound. Subjective assessment had the highest AUC (0.968), followed by the RMI (0.931) and the ROMA (0.893). Based on these results we concluded that ultrasound, especially subjective assessment by ultrasound, remains superior in discriminating malignant from benign ovarian masses. In an exploratory study we investigated whether endorepellin, an angiostatic peptide, could be used as a tumour marker for the differentiation between benign and malignant ovarian masses. This international cohort study was conducted in Belgium, Czech Republic, Sweden, and Italy. In postmenopausal women, all best performing panels included endorepellin with the highest AUC (0.920) for the triple combination of CA125, HE4 and endorepellin. Endorepellin also performed well in stage I and LMP tumours. These results need to be validated. Currently, the triple combination model is being validated in an independent study. The second diagnostic problem is the diagnosis of positive lymph nodes in cervical cancer. Lymph node involvement is a strong prognostic factor for cervical cancer. There is a strong need for biomarkers that predict lymph node involvement in cervical cancer. After depletion and SELDITOF MS analysis we were able to predict lymph node involvement with an AUC of 0.95. However, the attempts to identify the proteins behind the differentially expressed peaks were unsuccessful. Finally, the literature was critically reviewed and commented. It can be noticed that, although a lot of efforts have been put into global proteomics, none of the efforts have paid off. To date proteomic studies have not been able to change clinical practice.status: Publishe
Evidence of a genetic link between endometriosis and ovarian cancer
No full textTo evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer.sponsorship: This work was supported by the National Cancer Institute (K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, P50-CA105009, P50-CA136393, R01-CA149429, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080978, R01CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, and Intramural research funds); the European Commission's Seventh Framework Programme (agreement number 223175 HEALTH F2 2009-223175); a National Cancer Institute, Cancer Post-GWAS Initiative (U19-CA148112); the Genetic Associations and Mechanisms in Oncology (GAME-ON); the Ovarian Cancer Research Fund (thanks to donations by the family and friends of Kathryn Sladek Smith) (PPD/RPCI.07); the National Institute of Environmental Health Sciences (T32ES013678 to A.W.L.); National Health and Medical Research Council (to G.-C.T.); American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN to B.K.); National Center for Advancing Translational Sciences (NCATS) (UL1TR000124 to B.K.); California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes of Health Research (MOP-86727); Cancer Australia; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124); the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the National Institutes of Health/National Center for Research Resources/General Clinical Research Center (MO1-RR000056); the US Army Medical Research and Material Command (DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802); the U.S. Public Health Service (PSA-042205); the National Health and Medical Research Council of Australia (199600, 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.685); the German Cancer Research Center; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the Oregon Health & Science University Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital ''Womens Health Theme'' and the Royal Marsden Hospital; and WorkSafeBC 14. (National Cancer Institute|P50-CA105009, National Cancer Institute|P50-CA136393, National Cancer Institute|R01-CA149429, National Cancer Institute|R01-CA014089, National Cancer Institute|R01-CA016056, National Cancer Institute|R01-CA017054, National Cancer Institute|R01-CA049449, National Cancer Institute|R01-CA050385, National Cancer Institute|R01-CA054419, European Commission's Seventh Framework Programme|223175 HEALTH F2 2009-223175, National Cancer Institute, Cancer Post-GWAS Initiative|U19-CA148112, Genetic Associations and Mechanisms in Oncology (GAME-ON), Ovarian Cancer Research Fund|PPD/RPCI.07, National Institute of Environmental Health Sciences|T32ES013678, National Health and Medical Research Council, American Cancer Society Early Detection Professorship|SIOP-06-258-01-COUN, National Center for Advancing Translational Sciences (NCATS)|UL1TR000124, California Cancer Research Program|00-01389V-20170, California Cancer Research Program|N01-CN25403, California Cancer Research Program|2II0200, Canadian Institutes of Health Research|MOP-86727, Cancer Australia, Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, Cancer Council Tasmania, Cancer Foundation of Western Australia, Cancer Institute of New Jersey, Cancer Research UK|C490/A6187, Cancer Research UK|C490/A10119, Cancer Research UK|C490/A10124, Danish Cancer Society|94-222-52, ELAN Program of the University of Erlangen-Nuremberg, Eve Appeal, Helsinki University Central Hospital Research Fund, Helse Vest, Norwegian Cancer Society, Norwegian Research Council, Ovarian Cancer Research Fund, Nationaal Kankerplan of Belgium, L & S Milken Foundation, Polish Ministry of Science and Higher Education|4 PO5C 028 14, Polish Ministry of Science and Higher Education|2 PO5A 068 27, Roswell Park Cancer Institute Alliance Foundation, National Institutes of Health/National Center for Research Resources/General Clinical Research Center|MO1-RR000056, US Army Medical Research and Material Command|DAMD17-01-1-0729, US Army Medical Research and Material Command|DAMD17-02-1-0666, US Army Medical Research and Material Command|DAMD17-02-1-0669, US Army Medical Research and Material Command|W81XWH-07-0449, US Army Medical Research and Material Command|W81XWH-10-1-02802, U.S. Public Health Service|PSA-042205, National Health and Medical Research Council of Australia|199600, National Health and Medical Research Council of Australia|400281, German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research|01 GB 9401, State of Baden-Wurttemberg through Medical Faculty of the University of Ulm|P.685, German Cancer Research Center, Minnesota Ovarian Cancer Alliance, Mayo Foundation, Fred C. and Katherine B. Andersen Foundation, Lon V. Smith Foundation|LVS-39420, Oak Foundation, Oregon Health & Science University Foundation, Mermaid I project, Rudolf-Bartling Foundation, UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital ''Womens Health Theme'', Royal Marsden Hospital, WorkSafeBC 14, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080978, R01CA083918, R01-CA087538, R01-CA092044, R01-CA095023, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R03-CA113148, R03-CA115195, U01-CA069417, U01-CA071966, K07-CA095666, K07-CA80668, K07-CA143047, K22-CA138563, N01-CN55424, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA072720, P30-CA15083, P30-CA008748, P50-CA159981, Cancer Research UK|16561, Cancer Research UK; The Francis Crick Institute|10124, National Cancer Institute|ZIACP010126, National Cancer Institute|P30CA046592)status: Publishe
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