12 results on '"Iben Lyskjær"'
Search Results
2. MYC amplifications are common events in childhood osteosarcoma
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Anna Christina Strobl, Tim H. H. Coorens, Adrienne M. Flanagan, Solange De Noon, Sam Behjati, Iben Lyskjaer, Jannat Ijaz, Fernanda Amary, and Hongtao Ye
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Adult ,Male ,Aging ,Adolescent ,Genes, myc ,Genomics ,MYC ,Biology ,Pathology and Forensic Medicine ,Childhood Osteosarcoma ,osteosarcoma ,Cyclin E ,medicine ,genomics ,Pathology ,Humans ,RB1-214 ,Copy-number variation ,Child ,Index case ,Aged ,Aged, 80 and over ,Oncogene Proteins ,Oncogene ,Brief Report ,Gene Amplification ,Middle Aged ,medicine.disease ,CCNE1 ,Child, Preschool ,Cancer research ,Osteosarcoma ,Brief Reports ,Female ,copy number variants - Abstract
Osteosarcoma, the most common primary malignant tumour of bone, affects both children and adults. No fundamental biological differences between paediatric and adult osteosarcoma are known. Here, we apply multi‐region whole‐genome sequencing to an index case of a 4‐year‐old child whose aggressive tumour harboured high‐level, focal amplifications of MYC and CCNE1 connected by translocations. We reanalysed copy number readouts of 258 cases of high‐grade osteosarcoma from three different cohorts and identified a significant enrichment of focal MYC, but not CCNE1, amplifications in children. Furthermore, we identified four additional cases of MYC and CCNE1 coamplification, highlighting a rare driver event which warrants further investigation. Our findings indicate that amplification of the MYC oncogene is a major driver of childhood osteosarcoma, while CCNE1 appears recurrently amplified independent of age.
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- 2021
3. Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations
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Paul O'Donnell, Radhesh K Lalam, Steven James, Geoff Hide, Christopher Davies, Roberto Tirabosco, Jonathan Stevenson, Adrienne M. Flanagan, Paul Cool, Iben Lyskjaer, Joanna Hindley, Lee Jeys, William Cross, Anna-Christina Strobl, and Kenneth S. Rankin
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,IDH1 ,IDH2 ,Risk Assessment ,Circulating Tumor DNA ,RC0254 ,chemistry.chemical_compound ,GNAS ,Internal medicine ,Genetics ,medicine ,GNAS complex locus ,Biomarkers, Tumor ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Blood test ,Humans ,RC254-282 ,Research Articles ,chondrosarcoma ,medicine.diagnostic_test ,biology ,Bone cancer ,business.industry ,circulating tumour DNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,R735 ,General Medicine ,medicine.disease ,Isocitrate Dehydrogenase ,chemistry ,Mutation ,biology.protein ,Molecular Medicine ,Biomarker (medicine) ,prognosis ,Chondrosarcoma ,business ,DNA ,Research Article - Abstract
Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi‐institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre‐operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high‐grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard‐of‐care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS., In this multi‐institutional study, we detected the amount of circulating tumour DNA (ctDNA) in the blood of patients with chondrosarcoma. We recruited 145 patients, and ctDNA levels were assessed in patients with tumours carrying IDH1/2 or GNAS mutations. We found that ctDNA levels offered a more accurate identification of high‐grade tumours than pathology and were additionally associated with poor prognosis.
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- 2021
4. Osteosarcoma: Novel prognostic biomarkers using circulating and cell-free tumour DNA
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Iben Lyskjær, Neesha Kara, Solange De Noon, Christopher Davies, Ana Maia Rocha, Anna-Christina Strobl, Inga Usher, Craig Gerrand, Sandra J Strauss, Daniel Schrimpf, Andreas von Deimling, Stephan Beck, and Adrienne M Flanagan
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Osteosarcoma ,Cancer Research ,DNA methylation ,Adolescent ,Liquid biopsy ,Prognosis ,Circulating Tumor DNA ,Epigenetic biomarkers ,Oncology ,Mutation ,Biomarkers, Tumor ,Humans ,Epigenetics ,Child ,Circulating tumour DNA - Abstract
Aim: Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Circulating free (cfDNA) and circulating tumour DNA (ctDNA) are promising biomarkers for disease surveillance and prognostication in several cancer types; however, few such studies are reported for OS. The purpose of this study was to discover and validate methylation-based biomarkers to detect plasma ctDNA in patients with OS and explore their utility as prognostic markers. Methods: Candidate CpG markers were selected through analysis of methylation array data for OS, non-OS tumours and germline samples. Candidates were validated in two independent OS datasets (n = 162, n = 107) and the four top-performing markers were selected. Methylation-specific digital droplet PCR (ddPCR) assays were designed and experimentally validated in OS tumour samples (n = 20) and control plasma samples. Finally, ddPCR assays were applied to pre-operative plasma and where available post-operative plasma from 72 patients with OS, and findings correlated with outcome. Results: Custom ddPCR assays detected ctDNA in 69% and 40% of pre-operative plasma samples (n = 72), based on thresholds of one or two positive markers respectively. ctDNA was detected in 5/17 (29%) post-operative plasma samples from patients, which in four cases were associated with or preceded disease relapse. Both pre-operative cfDNA levels and ctDNA detection independently correlated with overall survival (p = 0.0015 and p = 0.0096, respectively). Conclusion: Our findings illustrate the potential of mutation-independent methylation-based ctDNA assays for OS. This study lays the foundation for multi-institutional collaborative studies to explore the utility of plasma-derived biomarkers in the management of OS.
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- 2022
5. A genetic model for central chondrosarcoma evolution correlates with patient outcome
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William, Cross, Iben, Lyskjær, Tom, Lesluyes, Steven, Hargreaves, Anna-Christina, Strobl, Christopher, Davies, Sara, Waise, Shadi, Hames-Fathi, Dahmane, Oukrif, Hongtao, Ye, Fernanda, Amary, Roberto, Tirabosco, Craig, Gerrand, Toby, Baker, David, Barnes, Christopher, Steele, Ludmil, Alexandrov, Gareth, Bond, Paul, Cool, Nischalan, Pillay, Peter, Van Loo, and Adrienne M, Flanagan
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Adult ,Models, Genetic ,Mutation ,Chondrosarcoma ,Humans ,Bone Neoplasms ,Prognosis ,Isocitrate Dehydrogenase ,Aged - Abstract
Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations.In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings.IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group.Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.
- Published
- 2021
6. DNA methylation-based profiling of bone and soft tissue tumours: a validation study of the 'DKFZ Sarcoma Classifier'
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Solange De Noon, Ana Maia Rocha, Damian Stichel, Iben Lyskjaer, Hongtao Ye, Daniel Schrimpf, Daniel Lindsay, Adrienne M. Flanagan, Nischalan Pillay, Stephan Beck, Martin Sill, Christian Koelsche, Roberto Tirabosco, Fernanda Amary, and Andreas von Deimling
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Pathology ,medicine.medical_specialty ,Soft Tissue Neoplasm ,sarcoma ,Bone Neoplasms ,Soft Tissue Neoplasms ,methylation profiling ,bone ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Biomarkers, Tumor ,RB1-214 ,Medicine ,Humans ,Medical diagnosis ,classifier ,business.industry ,Brain Neoplasms ,Fibrous dysplasia ,Gene Expression Profiling ,Soft tissue ,Original Articles ,DNA Methylation ,medicine.disease ,Classification ,Genetic Techniques ,DNA methylation ,Original Article ,Sarcoma ,business ,soft tissue ,Classifier (UML) ,Clear cell - Abstract
Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation‐based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the ‘DKFZ Sarcoma Classifier’ was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool.
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- 2021
7. Sarcoma classification by DNA methylation profiling
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Damian Stichel, Laura Romero-Pérez, Till Milde, Stefan Fröhling, Matija Snuderl, Florian Selt, Dominik Sturm, Kenneth Tou En Chang, Francisco Fernández-Klett, Sharon Yin Yee Low, Iben Lyskjaer, Marcel Kool, Wolfgang Hartmann, Adrian Cuevas-Bourdier, Simon Kreutzfeldt, Cristina R. Antonescu, Christoph Heining, Jürgen Hench, Adrienne M. Flanagan, Rolf Buslei, Gunhild Mechtersheimer, Jonas Ecker, Daniel Schrimpf, Amir Abdollahi, David Capper, Thomas Mentzel, Uta Flucke, Olaf Witt, Matthias Schick, Mark Kriegsmann, Christian Thomas, Felix Sahm, Andreas von Deimling, Jaume Mora, Pieter Wesseling, Eva Wardelmann, Sebastian Stark, Annika K. Wefers, Christian Koelsche, Marc Ladanyi, Benedikt Brors, Manfred Gessler, Winand N.M. Dinjens, David T.W. Jones, Jonathan Serrano, Jamal Benhamida, Jens Schittenhelm, Azadeh Ebrahimi, Christian Vokuhl, Thomas G. P. Grunewald, Hanno Glimm, Annekathrin Reinhardt, Manel Esteller, Juan Díaz Martín, Peter Schirmacher, Belen Casalini, Iver Petersen, Abigail K. Suwala, Jürgen Debus, Javier Alonso, Stephan Frank, Martin Sill, Martin Mynarek, Miguel Angel Idoate Gastearena, Michael Platten, Matthias Uhl, Michel Mittelbronn, Sebastian Moran, Stefan M. Pfister, Christian Hartmann, Daniel Baumhoer, Melanie Bewerunge-Hudler, Reinhard Büttner, Volker Hovestadt, Pascal Johann, Oscar M. Tirado, Philipp Sievers, Burkhard Lehner, Elke Paff, Werner Paulus, Albrecht Stenzinger, Andrey Korshunov, Marije E. Weidema, Enrique de Álava, V. F. Mautner, Andreas Unterberg, Kristian W. Pajtler, Klaus G. Griewank, Xavier Garcia del Muro, Wolfgang Wick, David E. Reuss, Thomas Klingebiel, Andreas E. Kulozik, Sebastian Brandner, Ori Staszewski, Yvonne M.H. Versleijen-Jonkers, Mirjam Blattner, Christoph E. Heilig, Stefan Rutkowski, Barbara C. Worst, Thomas Kirchner, Katja Beck, Peter Horak, Ulrich Schüller, Zane Jaunmuktane, Peter Hohenberger, Marco Prinz, Uta Dirksen, Miguel Sáinz-Jaspeado, Felix K. F. Kommoss, Martin Hasselblatt, Pathology, CCA - Imaging and biomarkers, German Cancer Aid, National Institute for Health Research (Reino Unido), NIHR - UCL Biomedical Research Centre (Reino Unido), Luxembourg National Research Fund, National Center for Tumor Diseases (Germany), National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Medical Research Council (UK), Brain Archive Information Network (UK), Brain Tumour Research, Friedberg Charitable Foundation, Fonds National de la Recherche Luxembourg, Projekt DEAL, Deutsche Krebshilfe, National Institute for Health Research (United Kingdom), and UCLH Biomedical research centre
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Soft Tissue Neoplasm ,DNA Copy Number Variations ,Classification and taxonomy ,Science ,ADN ,Medizin ,General Physics and Astronomy ,Bone Neoplasms ,Soft Tissue Neoplasms ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Bone Sarcoma ,Biology ,Sensitivity and Specificity ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,Machine Learning ,Databases ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,medicine ,Humans ,Internet ,Multidisciplinary ,Soft tissue ,Reproducibility of Results ,Sarcoma ,General Chemistry ,Methylation ,DNA ,DNA Methylation ,medicine.disease ,Computational biology and bioinformatics ,Dna methylation profiling ,030104 developmental biology ,030220 oncology & carcinogenesis ,DNA methylation ,Classifier (UML) ,Algorithms - Abstract
Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications., This work was funded by Deutsche Krebshilfe grant 70112499, the NCT Heidelberg and an Illumina Medical Research Grant. Part of this work was funded by the National Institute of Health Research (to S.B. and Z.J.) and to UCLH Biomedical research centre (BRC399/NS/RB/101410). Human tissues were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 18/004) which is funded by the Medical Research Council and Brain Tumour Research UK. The methylation profiling at NYU is supported by a grant from the Friedberg Charitable Foundation (to M.Sn.). M.Mi. would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant). Open Access funding enabled and organized by Projekt DEAL.
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- 2021
8. Drivers underpinning the malignant transformation of giant cell tumour of bone
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Iben Lyskjaer, Roberto Tirabosco, Peter Ellery, Jonas Demeulemeester, Anna Christina Strobl, Matthew Fittall, David T.W. Jones, Christian Koelsche, Sam Behjati, Gunhild Mechtersheimer, Dahmane Oukrif, Fernanda Amary, Nischalan Pillay, Peter Van Loo, Peter J. Campbell, Maxime Tarabichi, Jannat Ijaz, Stefan M. Pfister, Patrick Lombard, Martin Sill, and Adrienne M. Flanagan
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0301 basic medicine ,sarcoma ,cyclin D1 ,Aneuploidy ,Bone Neoplasms ,histone ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,bone ,Pathology and Forensic Medicine ,Malignant transformation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,genomics ,Humans ,Promoter Regions, Genetic ,Gene ,Epigenomics ,Giant Cell Tumor of Bone ,Original Paper ,Mutation ,Whole Genome Sequencing ,biology ,transformation ,Cancer ,drivers ,Methylation ,DNA Methylation ,medicine.disease ,Original Papers ,Cell Transformation, Neoplastic ,030104 developmental biology ,Histone ,Giant cell ,030220 oncology & carcinogenesis ,DNA methylation ,osteoclast ,Mutation (genetic algorithm) ,osteoblast ,biology.protein ,Cancer research ,methylation ,epigenetic ,giant cell tumour - Abstract
The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. ispartof: JOURNAL OF PATHOLOGY vol:252 issue:4 pages:433-440 ispartof: location:England status: published
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- 2020
9. Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer
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Amanda Frydendahl Boll Johansen, Karen-Lise Garm Spindler, Iben Lyskjær, Camilla Kronborg, Boe Sandahl Sorensen, Claus L. Andersen, Søren Krag, Mads Rasmussen, Christina Demuth, Søren Vang, Michael Knudsen, and Mona Rosenkilde
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0301 basic medicine ,Oncology ,Male ,Colorectal cancer ,Leucovorin ,lcsh:Medicine ,GUIDELINES ,THERAPY ,Circulating Tumor DNA ,Correlation ,Tumour biomarkers ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Neoplasm Metastasis ,lcsh:Science ,Aged, 80 and over ,Multidisciplinary ,PLASMA ,Middle Aged ,Response to treatment ,Progression-Free Survival ,Treatment Outcome ,FOLFIRI ,SURVIVAL ,Female ,Fluorouracil ,Colorectal Neoplasms ,Cell-Free Nucleic Acids ,Adult ,medicine.medical_specialty ,Early detection ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Biomarkers, Tumor ,Chemotherapy ,Humans ,Progression-free survival ,Aged ,DIGITAL PCR ,business.industry ,MUTATIONS ,lcsh:R ,medicine.disease ,030104 developmental biology ,chemistry ,Mutation ,lcsh:Q ,Camptothecin ,business ,030217 neurology & neurosurgery ,Progressive disease ,DNA ,ACQUIRED-RESISTANCE - Abstract
Chemotherapy resistance remains a challenge in the clinical management of metastatic colorectal cancer (mCRC). Here, early changes in cell-free circulating tumour DNA (ctDNA) levels were explored as a marker of therapeutic efficacy. Twenty-four mCRC patients were enrolled and treated with FOLFIRI based first-line therapy. Blood samples collected pre-treatment, at day 7, 14, 21, 60 and at progression were analysed for cell-free DNA (cfDNA) and ctDNA levels using digital droplet PCR. A subset of samples were additionally analysed by targeted sequencing. Patients with high pre-treatment ctDNA or cfDNA levels (≥75th centile) had significantly shorter progression free survival (PFS) than patients with lower levels. Despite an overall decline in ctDNA levels from pre-treatment to first CT-scan, serial analysis identified seven patients with temporary increases in ctDNA consistent with growth of resistant cells. These patients had shorter PFS and shorter overall survival. Targeted sequencing analyses of cfDNA revealed dramatic changes in the clonal composition in response to treatment. Our study suggests that increasing ctDNA levels during the first cycles of first-line FOLFIRI treatment is a predictor of incipient progressive disease and poorer survival. Thus, we demonstrate the importance of monitoring ctDNA levels as early as one week after treatment onset to enable early detection of treatment failure.
- Published
- 2019
10. miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells
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Iben Lyskjær, Per Pfeiffer, Tine Plato Hansen, Torben F. Ørntoft, Mads Rasmussen, Jakob Skou Pedersen, Line Schmidt Tarpgaard, Claus L. Andersen, Bjarke Primdal-Bengtson, Jesper V. Olsen, Flemming Hansen, Morten Muhlig Nielsen, and Rosa Rakownikow Jersie-Christensen
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0301 basic medicine ,Small interfering RNA ,Organoplatinum Compounds ,Proteome ,Science ,General Physics and Astronomy ,Antineoplastic Agents ,Apoptosis ,MAP Kinase Kinase 6 ,Drug resistance ,Adenocarcinoma ,Biology ,Bioinformatics ,p38 Mitogen-Activated Protein Kinases ,Article ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,03 medical and health sciences ,Cell Line, Tumor ,microRNA ,medicine ,Journal Article ,Humans ,Multidisciplinary ,Predictive marker ,Gene Expression Profiling ,HEK 293 cells ,General Chemistry ,HCT116 Cells ,digestive system diseases ,Oxaliplatin ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,HEK293 Cells ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,Ectopic expression ,Colorectal Neoplasms ,Signal Transduction ,medicine.drug - Abstract
Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed. Recently, miR-625-3p was reported as a promising predictive marker. Herein, we show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. We show that the p38 MAPK activator MAP2K6 is a direct target of miR-625-3p, and, accordingly, is downregulated in non-responder patients of oxaliplatin therapy. miR-625-3p-mediated resistance is reversed by anti-miR-625-3p treatment and ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, reduction of p38 signalling by using siRNAs, chemical inhibitors or expression of a dominant-negative MAP2K6 protein induces resistance to oxaliplatin. Transcriptome, proteome and phosphoproteome profiles confirm inactivation of MAP2K6-p38 signalling as one likely mechanism of oxaliplatin resistance. Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p., Oxaliplatin resistance in colorectal cancers is a major clinical problem, and predictive markers are urgently needed. Here, the authors show that miR-625-3p expression reduces the sensitivity of colorectal cancer cells to oxaliplatin by targeting the kinase MAP2K6, an activator of the MAPK14 pathway.
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- 2016
11. A genetically inducible porcine model of intestinal cancer
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Mai-Britt Worm Ørntoft, Martin F. Berthelsen, Kim B. Jensen, Claus L. Andersen, Søren Laurberg, Torben F. Ørntoft, Ying Liu, Martin K. Thomsen, Frederik Dagnæs-Hansen, Rong Li, Henrik Callesen, Søren Høyer, Morten M. Callesen, Iben Lyskjær, Pawel J. Schweiger, Mads Rasmussen, Jannik Ejnar Elverløv-Jakobsen, and Sigrid S. Árnadóttir
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0301 basic medicine ,Cancer Research ,Nuclear Transfer Techniques ,Swine ,Transgene ,Cloning, Organism ,Biology ,Metastasis ,Animals, Genetically Modified ,Embryo Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,transgenic porcine model ,In vivo ,Intestinal Neoplasms ,Genetics ,medicine ,Carcinoma ,Animals ,Humans ,Intestinal Mucosa ,Research Articles ,tissue‐specific activation ,Oncogene ,General Medicine ,medicine.disease ,Embryo Transfer ,idducible intestinal cancer ,tissue-specific activation ,Molecular biology ,In vitro ,Intestines ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Swine, Miniature ,oncopig ,Female ,inducible intestinal cancer ,Tamoxifen ,Ex vivo ,Inducible intestinal cancer ,medicine.drug ,Research Article - Abstract
Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4-OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 × 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis.
- Published
- 2017
12. Putting a brake on stress signaling - miR-625-3p as a biomarker for choice of therapy in colorectal cancer
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Claus L. Andersen, Mads Rasmussen, and Iben Lyskjær
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0301 basic medicine ,Cancer Research ,Organoplatinum Compounds ,Colorectal cancer ,Biology ,Irinotecan ,03 medical and health sciences ,Stress, Physiological ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Genetics ,medicine ,Animals ,Humans ,RNA, Neoplasm ,Stress signaling ,medicine.disease ,Oxaliplatin ,MicroRNAs ,030104 developmental biology ,Cancer research ,Biomarker (medicine) ,Camptothecin ,Fluorouracil ,Colorectal Neoplasms ,Signal Transduction ,medicine.drug - Published
- 2016
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