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  • 1
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    Online Resource
    H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours
    Wiley ; 2020
    In:  The Journal of Pathology Vol. 252, No. 2 ( 2020-10), p. 151-164
    Details
    In: The Journal of Pathology, Wiley, Vol. 252, No. 2 ( 2020-10), p. 151-164
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.v252.2
    DOI: 10.1002/path.5507
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1475280-3
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  • 2
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    Activating mutations in the MAP‐kinase pathway define non‐ossifying fibroma of bone
    Wiley ; 2019
    In:  The Journal of Pathology Vol. 248, No. 1 ( 2019-05), p. 116-122
    Details
    In: The Journal of Pathology, Wiley, Vol. 248, No. 1 ( 2019-05), p. 116-122
    Abstract: Non‐ossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and self‐limiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS , FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAP‐kinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRAS ‐ and MAP‐kinase signalling‐driven tumours. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2019.248.issue-1
    DOI: 10.1002/path.5216
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1475280-3
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  • 3
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    Circulating tumour DNA is a promising biomarker for risk stratification of central chondrosarcoma with IDH1/2 and GNAS mutations
    Wiley ; 2021
    In:  Molecular Oncology Vol. 15, No. 12 ( 2021-12), p. 3679-3690
    Details
    In: Molecular Oncology, Wiley, Vol. 15, No. 12 ( 2021-12), p. 3679-3690
    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.
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.v15.12
    DOI: 10.1002/1878-0261.13102
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2322586-5
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  • 4
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    Online Resource
    Sarcoma and the 100,000 Genomes Project: our experience and changes to practice
    Wiley ; 2020
    In:  The Journal of Pathology: Clinical Research Vol. 6, No. 4 ( 2020-10), p. 297-307
    Details
    In: The Journal of Pathology: Clinical Research, Wiley, Vol. 6, No. 4 ( 2020-10), p. 297-307
    Abstract: The largest whole genome sequencing (WGS) endeavour involving cancer and rare diseases was initiated in the UK in 2015 and ran for 5 years. Despite its rarity, sarcoma ranked third overall among the number of patients' samples sent for sequencing. Herein, we recount the lessons learned by a specialist sarcoma centre that recruited close to 1000 patients to the project, so that we and others may learn from our experience. WGS data was generated from 597 patients, but samples from the remaining approximately 400 patients were not sequenced. This was largely accounted for by unsuitability due to extensive necrosis, secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in formalin. The number of informative genomes produced was reduced further by a PCR amplification step. We showed that this loss of genomic data could be mitigated by sequencing whole genomes from needle core biopsies. Storage of resection specimens at 4 °C for up to 96 h overcame the challenge of freezing tissue out of hours including weekends. Removing access to formalin increased compliance to these storage arrangements. With over 70 different sarcoma subtypes described, WGS was a useful tool for refining diagnoses and identifying novel alterations. Genomes from 350 of the cohort of 597 patients were analysed in this study. Overall, diagnoses were modified for 3% of patients following review of the WGS findings. Continued refinement of the variant‐calling bioinformatic pipelines is required as not all alterations were identified when validated against histology and standard of care diagnostic tests. Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the WGS exhibiting domain 1 alterations, the number of patients with sarcoma who were eligible for clinical trials remains small, highlighting the need to revaluate clinical trial design.
    Type of Medium: Online Resource
    ISSN: 2056-4538 , 2056-4538
    URL: Issue
    URL: Article
    DOI: 10.1002/cjp2.v6.4
    DOI: 10.1002/cjp2.174
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2814357-7
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  • 5
    Online Resource
    Online Resource
    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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  • 6
    Online Resource
    Online Resource
    Duplication Xp11.22‐p14 in females: Does X‐inactivation help in assessing their significance?
    Wiley ; 2015
    In:  American Journal of Medical Genetics Part A Vol. 167, No. 3 ( 2015-03), p. 553-562
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 167, No. 3 ( 2015-03), p. 553-562
    Abstract: In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22‐p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22‐p11.23, her phenotype and X‐chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23‐p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23‐p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1–5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. © 2015 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v167.3
    DOI: 10.1002/ajmg.a.36897
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1493479-6
    SSG: 12
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