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  • 11
    Online Resource
    Online Resource
    Subclassification of epithelioid sarcoma with potential therapeutic impact
    Wiley ; 2023
    In:  The Journal of Pathology Vol. 260, No. 4 ( 2023-08), p. 368-375
    Details
    In: The Journal of Pathology, Wiley, Vol. 260, No. 4 ( 2023-08), p. 368-375
    Abstract: Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1 , a key member of the SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1 ‐deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1‐ deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1 ‐deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1‐ deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8 + lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.v260.4
    DOI: 10.1002/path.6135
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1475280-3
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  • 12
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    Drivers underpinning the malignant transformation of giant cell tumour of bone
    Wiley ; 2020
    In:  The Journal of Pathology Vol. 252, No. 4 ( 2020-12), p. 433-440
    Details
    In: The Journal of Pathology, Wiley, Vol. 252, No. 4 ( 2020-12), p. 433-440
    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.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.v252.4
    DOI: 10.1002/path.5537
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1475280-3
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  • 13
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    Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-08-08)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-08-08)
    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 (≥75 th 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.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-47708-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 14
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    DNA methylation‐based profiling of bone and soft tissue tumours: a validation study of the ‘ DKFZ Sarcoma Classifier’
    Wiley ; 2021
    In:  The Journal of Pathology: Clinical Research Vol. 7, No. 4 ( 2021-07), p. 350-360
    Details
    In: The Journal of Pathology: Clinical Research, Wiley, Vol. 7, No. 4 ( 2021-07), p. 350-360
    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.
    Type of Medium: Online Resource
    ISSN: 2056-4538 , 2056-4538
    URL: Issue
    URL: Article
    DOI: 10.1002/cjp2.v7.4
    DOI: 10.1002/cjp2.215
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2814357-7
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  • 15
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    MYC amplifications are common events in childhood osteosarcoma
    Wiley ; 2021
    In:  The Journal of Pathology: Clinical Research Vol. 7, No. 5 ( 2021-09), p. 425-431
    Details
    In: The Journal of Pathology: Clinical Research, Wiley, Vol. 7, No. 5 ( 2021-09), p. 425-431
    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.
    Type of Medium: Online Resource
    ISSN: 2056-4538 , 2056-4538
    URL: Issue
    URL: Article
    DOI: 10.1002/cjp2.v7.5
    DOI: 10.1002/cjp2.219
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2814357-7
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  • 16
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    DREAMS: deep read-level error model for sequencing data applied to low-frequency variant calling and circulating tumor DNA detection
    Springer Science and Business Media LLC ; 2023
    In:  Genome Biology Vol. 24, No. 1 ( 2023-04-30)
    Details
    In: Genome Biology, Springer Science and Business Media LLC, Vol. 24, No. 1 ( 2023-04-30)
    Abstract: Circulating tumor DNA detection using next-generation sequencing (NGS) data of plasma DNA is promising for cancer identification and characterization. However, the tumor signal in the blood is often low and difficult to distinguish from errors. We present DREAMS (Deep Read-level Modelling of Sequencing-errors) for estimating error rates of individual read positions. Using DREAMS, we develop statistical methods for variant calling (DREAMS-vc) and cancer detection (DREAMS-cc). For evaluation, we generate deep targeted NGS data of matching tumor and plasma DNA from 85 colorectal cancer patients. The DREAMS approach performs better than state-of-the-art methods for variant calling and cancer detection.
    Type of Medium: Online Resource
    ISSN: 1474-760X
    URL: Article
    DOI: 10.1186/s13059-023-02920-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2040529-7
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  • 17
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    Abstract 2927: miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cell
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2927-2927
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2927-2927
    Abstract: Oxaliplatin (oxPt) 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. Here, we have used in vitro models to show that miR-625-3p functionally induces oxPt resistance in CRC cells, and have identified signalling networks affected by mir-625-3p. The p38 MAPK activator MAP2K6 was shown to be a direct target of miR-625-3p, and, accordingly, was downregulated in patients not responding to oxPt therapy. miR-625-3p resistance could be reversed in CRC cells by anti-miR-625-3p treatment and by ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, by reducing p38 MAPK signalling using either siRNA technology, chemical inhibitors to p38 or by ectopic expression of dominant negative MAP2K6 protein we induced resistance to oxPt. Transcriptome, proteome and phosphoproteome profiles revealed inactivation of MAP2K6-p38 signalling as a possible driving force behind oxPt resistance. Our study shows that miR-625-3p induces oxPt resistance by abrogating MAP2K6-p38 regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p. Citation Format: Mads H. Rasmussen, Iben Lyskjær, Rosa R. Jersie-Christensen, Line S. Tarpgaard, Bjarke Primdal-Bengtson, Morten M. Nielsen, Jakob S. Pedersen, Tine P. Hansen, Flemming Hansen, Jesper V. Olsen, Per Pfeiffer, Torben F. Ørntoft, Claus L. Andersen. miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2927.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2927
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 18
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    Putting a brake on stress signaling: miR-625-3p as a biomarker for choice of therapy in colorectal cancer
    Future Medicine Ltd ; 2016
    In:  Epigenomics Vol. 8, No. 11 ( 2016-11), p. 1449-1452
    Details
    In: Epigenomics, Future Medicine Ltd, Vol. 8, No. 11 ( 2016-11), p. 1449-1452
    Type of Medium: Online Resource
    ISSN: 1750-1911 , 1750-192X
    URL: Article
    DOI: 10.2217/epi-2016-0128
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2016
    SSG: 12
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