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

Lyskjær, I; Lindsay, D; Tirabosco, R; Steele, CD; Lombard, P; Strobl, A-C; Rocha, AM; ... Flanagan, AM; + view all (2020) H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours. The Journal of Pathology , 252 (2) pp. 151-164. 10.1002/path.5507. Green open access

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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 35–84%. We show that advances in molecular pathology now allows 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 distinguish MPNST from its histological mimics, was unrelated to anatomical site and formed two main clusters, MeGroup 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in the majority of cases, whereas MeGroup 5 comprise 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 MeGroup 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.

Type: Article
Title: H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/path.5507
Publisher version: https://doi.org/10.1002/path.5507
Language: English
Additional information: H3K27me3 expression and methylation status in histologicalvariants of malignant peripheral nerve sheath tumoursIben Lyskjær1, Daniel Lindsay1,2†, Roberto Tirabosco2†, Christopher D Steele1, Patrick Lombard1,Anna-Christina Strobl2, Ana M Rocha2, Christopher Davies2, Hongtao Ye2, Elise Bekers3, Julia Ingruber4,Matt Lechner5, Fernanda Amary1,2, Nischalan Pillay1,2and Adrienne M Flanagan1,2*1Research Department of Pathology, University College London, London, UK2Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, UK3Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands4Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria5UCL Cancer Institute, University College London, London, UK*Correspondence to: AM Flanagan, Research Department of Pathology, UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, LondonWC1E 6DD, UK. E-mail: a.anagan@ucl.ac.uk†These authors contributed equally to this work.AbstractDiagnosing MPNST can be challengin g, but genetic alteratio ns recent ly identi ed in polycomb repressivecomplex 2 ( PRC2) core component genes, EED and SUZ12, resulting in global loss of the histone 3 lysine27 trimethylation (H3K27me3) epigenetic mark, represent drivers of malignancy and a valuable diagnostictool. However, the reported loss of H3K27me3 expression ranges from 35% to 84%. We show that advancesin molecular pathology now allow many MPNST mimics to be classied condently . We conrm that MPNSTsharbouring mutations in PRC2 core components are associated with loss of H3K27me3 expression; whole-genome doubling was detected in 6 8%, and SSTR2 was amplied in 32% of MPNSTs. We de monstrate thatloss of H3K27me3 expression occurs overall in 38% of MPNSTs, but is lost in 76% of histologically classicalcases, whereas loss was detected in only 23% cases with heterologous elements and 14% where the diagnosiscould n ot be pr ovided on morphology alone. H3K27me3 lo ss is r arely seen in other high-g rade sar comas andwas not f ound to be associated with an inferior ou tcome in MPNS T. We show that DNA methy lation pro lingdistinguishes MPNST from its histological mimics, was unrelated to anatomical site, and formed two mainclusters, MeGroups 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in themajority of cases, whereas MeGroup 5 comprises MPNSTs exhibiting non-classical histology and expressingH3K27me3 and cluster with undifferentiated sarcomas. The two MeGroups are d istinguished by differentiallymethylated PRC2-associated genes, the majority of which are hypermethylated in the promoter regions inMeGroup 4, indicating that the PRC2 target genes are not expressed in these tumours. The methylation pro-les o f MPNST s with retention of H3K27me3 in MeGroups 4 and 5 are indepe ndent o f mutat ions in PRC2core components and the driver(s) in these groups remain to be ident ied. Our results open new a venues ofinvestigation.©2020TheAuthors.The Journal o f Pathology pu blished by John Wile y & Sons, Ltd. o n behalf of The Pathological Society ofGreat Britain and Ireland.Keywords: malignant peripheral nerve sheath tumours; H3K27me3; whole-exome sequencing; whole-genome sequencing; DNA methyla-tion; sarcoma; genome doubling; neurobromatosis type 1; RNA-sequencingReceived 16 March 2020; Revised 23 June 2020; Accepted 6 July 2020NP is an Associate Editor of The Journal of Pathology. AMF is currently President of The Pathological Society, owner of this Journal. No other potentialconicts of interest were declared.IntroductionMalignant peripheral nerve sheath tumours (MPNSTs)are characterised by nerve sheath differentiation andaccount for roughly 5% of all sarcoma subtypes[1]. Approximately 45% present in the context of neuro-bromatosis type-1 (NF-1), a germline tumourpredisposition syndrome (incidence 1/3,500) causedby constitutional mutations in the tumour suppressorgene neurobromin 1 (NF1); 45% of cases occur as spo-radic tumours and 10% are radiation-associated.MPNST has an aggressive clinical course, with 50%relapsing and an overall average 5-year survival rate of43% [2]. The classical variant of MPNST shows featuresJournal of PathologyJ Pathol October 2020; 252: 151–164Published online 1 September 2020 in Wiley Online Library(wileyonlinelibrary.com)DOI: 10.1002/path.5507ORIGINAL PAPER© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited.
Keywords: DNA methylation, H3K27me3, Malignant Peripheral Nerve Sheath Tumours, genome doubling, neurofibromatosis type 1, sarcoma, whole exome sequencing, whole genome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10106206
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