title: Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas. Additional diagnostic markers are needed to aid in this often challenging differential diagnosis. Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED, were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases. Furthermore, both SUZ12 and EED mutations in MPNSTs were associated with loss of H3K27 tri-methylation, a downstream target of PRC2. Therefore, we tested whether H3K27me3 immunohistochemistry is useful as a diagnostic and prognostic marker for MPNSTs. We performed H3K27me3 immunohistochemistry in 162 primary MPNSTs, 97 neurofibromas and 341 other tumors using tissue microarray. We observed loss of H3K27me3 in 34% (55/162) of all MPNSTs while expression was retained in all neurofibromas including atypical (n=8) and plexiform subtypes (n=24). Within other tumors we detected loss of H3K27me3 in only 7% (24/341). Surprisingly, 60% (9/15) of synovial sarcomas and 38% (3/8) of fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) showed loss of H3K27 trimethylation. Only 1 out of 44 schwannomas showed loss of H3K27me3 and all 4 perineuriomas showed intact H3K27me3. Furthermore, MPNSTs with loss of H3K27 tri-methylation showed inferior survival compared with MPNSTs with intact H3K27 tri-methylation, which was validated in two independent cohorts. Our results indicate that H3K27me3 immunohistochemistry is useful as a diagnostic marker, in which loss of H3K27me3 favors MPNST above neurofibroma. However, H3K27me3 immunohistochemistry is not suitable to distinguish MPNST from its morphological mimicker synovial sarcoma or fibrosarcomatous DFSP. Since loss of H3K27 tri-methylation was related to poorer survival in MPNST, chromatin modification mediated by this specific histone seems to orchestrate more aggressive tumour biology.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arjen H G
authors.initials: AH
authors.lastname: Cleven
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ghadah A Al
authors.initials: GA
authors.lastname: Sannaa
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Briaire-de Bruijn
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Davis R
authors.initials: DR
authors.lastname: Ingram
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.affiliation: Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic and Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Otolaryngology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maurits W
authors.initials: MW
authors.lastname: de Vries
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Watson
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keila E
authors.initials: KE
authors.lastname: Torres
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: van Duinen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002140:California; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D003937:Diagnosis, Differential; D005260:Female; D006657:Histones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008239:Lysine; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009442:Neurilemmoma / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D013781:Texas; D013997:Time Factors; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D006657:Histones; D008239:Lysine