Publications by authors named "Iben Lyskjaer"

7 Publications

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Sarcoma classification by DNA methylation profiling.

Authors:
Christian Koelsche Daniel Schrimpf Damian Stichel Martin Sill Felix Sahm David E Reuss Mirjam Blattner Barbara Worst Christoph E Heilig Katja Beck Peter Horak Simon Kreutzfeldt Elke Paff Sebastian Stark Pascal Johann Florian Selt Jonas Ecker Dominik Sturm Kristian W Pajtler Annekathrin Reinhardt Annika K Wefers Philipp Sievers Azadeh Ebrahimi Abigail Suwala Francisco Fernández-Klett Belén Casalini Andrey Korshunov Volker Hovestadt Felix K F Kommoss Mark Kriegsmann Matthias Schick Melanie Bewerunge-Hudler Till Milde Olaf Witt Andreas E Kulozik Marcel Kool Laura Romero-Pérez Thomas G P Grünewald Thomas Kirchner Wolfgang Wick Michael Platten Andreas Unterberg Matthias Uhl Amir Abdollahi Jürgen Debus Burkhard Lehner Christian Thomas Martin Hasselblatt Werner Paulus Christian Hartmann Ori Staszewski Marco Prinz Jürgen Hench Stephan Frank Yvonne M H Versleijen-Jonkers Marije E Weidema Thomas Mentzel Klaus Griewank Enrique de Álava Juan Díaz Martín Miguel A Idoate Gastearena Kenneth Tou-En Chang Sharon Yin Yee Low Adrian Cuevas-Bourdier Michel Mittelbronn Martin Mynarek Stefan Rutkowski Ulrich Schüller Viktor F Mautner Jens Schittenhelm Jonathan Serrano Matija Snuderl Reinhard Büttner Thomas Klingebiel Rolf Buslei Manfred Gessler Pieter Wesseling Winand N M Dinjens Sebastian Brandner Zane Jaunmuktane Iben Lyskjær Peter Schirmacher Albrecht Stenzinger Benedikt Brors Hanno Glimm Christoph Heining Oscar M Tirado Miguel Sáinz-Jaspeado Jaume Mora Javier Alonso Xavier Garcia Del Muro Sebastian Moran Manel Esteller Jamal K Benhamida Marc Ladanyi Eva Wardelmann Cristina Antonescu Adrienne Flanagan Uta Dirksen Peter Hohenberger Daniel Baumhoer Wolfgang Hartmann Christian Vokuhl Uta Flucke Iver Petersen Gunhild Mechtersheimer David Capper David T W Jones Stefan Fröhling Stefan M Pfister Andreas von Deimling

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Drivers underpinning the malignant transformation of giant cell tumour of bone.

J Pathol 2020 Dec 6;252(4):433-440. Epub 2020 Oct 6.

Department of Pathology (research), University College London Cancer Institute, London, UK.

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.
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http://dx.doi.org/10.1002/path.5537DOI Listing
December 2020

H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours.

J Pathol 2020 10 1;252(2):151-164. Epub 2020 Sep 1.

Research Department of Pathology, University College London, London, UK.

Diagnosing MPNST can be challenging, but genetic alterations recently identified in polycomb repressive complex 2 (PRC2) core component genes, EED and SUZ12, resulting in global loss of the histone 3 lysine 27 trimethylation (H3K27me3) epigenetic mark, represent drivers of malignancy and a valuable diagnostic tool. However, the reported loss of H3K27me3 expression ranges from 35% to 84%. We show that advances in molecular pathology now allow many MPNST mimics to be classified confidently. We confirm that MPNSTs harbouring mutations in PRC2 core components are associated with loss of H3K27me3 expression; whole-genome doubling was detected in 68%, and SSTR2 was amplified in 32% of MPNSTs. We demonstrate that loss of H3K27me3 expression occurs overall in 38% of MPNSTs, but is lost in 76% of histologically classical cases, whereas loss was detected in only 23% cases with heterologous elements and 14% where the diagnosis could not be provided on morphology alone. H3K27me3 loss is rarely seen in other high-grade sarcomas and was not found to be associated with an inferior outcome in MPNST. We show that DNA methylation profiling distinguishes MPNST from its histological mimics, was unrelated to anatomical site, and formed two main clusters, MeGroups 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in the majority of cases, whereas MeGroup 5 comprises MPNSTs exhibiting non-classical histology and expressing H3K27me3 and cluster with undifferentiated sarcomas. The two MeGroups are distinguished by differentially methylated PRC2-associated genes, the majority of which are hypermethylated in the promoter regions in MeGroup 4, indicating that the PRC2 target genes are not expressed in these tumours. The methylation profiles of MPNSTs with retention of H3K27me3 in MeGroups 4 and 5 are independent of mutations in PRC2 core components and the driver(s) in these groups remain to be identified. Our results open new avenues of investigation. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5507DOI Listing
October 2020

Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer.

Sci Rep 2019 08 8;9(1):11542. Epub 2019 Aug 8.

Department of Molecular Medicine, Aarhus University Hospital, DK-8200, Aarhus, Denmark.

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 (≥75 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.
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http://dx.doi.org/10.1038/s41598-019-47708-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687711PMC
August 2019

A genetically inducible porcine model of intestinal cancer.

Mol Oncol 2017 11 10;11(11):1616-1629. Epub 2017 Oct 10.

Department of Molecular Medicine, Aarhus University Hospital, Denmark.

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.
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http://dx.doi.org/10.1002/1878-0261.12136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664002PMC
November 2017

Putting a brake on stress signaling: miR-625-3p as a biomarker for choice of therapy in colorectal cancer.

Epigenomics 2016 11 25;8(11):1449-1452. Epub 2016 Oct 25.

Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.

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http://dx.doi.org/10.2217/epi-2016-0128DOI Listing
November 2016

miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells.

Nat Commun 2016 08 16;7:12436. Epub 2016 Aug 16.

Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.

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.
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http://dx.doi.org/10.1038/ncomms12436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990699PMC
August 2016