Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft tissue sarcomas that can occur sporadically or in the setting of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. These tumors carry a dismal overall survival. Previous work in our lab had identified ATRX chromatin remodeler (ATRX), previously termed, Alpha Thalassemia/Mental Retardation Syndrome X Linked as a gene mutated in a subset of MPNSTs. Given the great need for novel biomarkers and therapeutic targets for MPNSTs, we sought to determine the expression of ATRX in a larger subset of sporadic and NF1 associated MPNSTs (NF1-MPNSTs). We performed immunohistochemistry (IHC) on 74 MPNSTs (43 NF1-associated and 31 sporadic), 21 plexiform neurofibromas, and 9 atypical neurofibromas. Using this approach, we have demonstrated that 58% (43/74) of MPNSTs have aberrant ATRX expression (<80% nuclear expression) compared to only 7% (2/30) of benign (plexiform and atypical) neurofibromas. Second, we demonstrated that 65% (28/43) of NF1-MPNSTs displayed aberrant ATRX expression as did 48% (15/31) of sporadic MPNSTs. Finally, we show that aberrant ATRX expression was associated with a significantly decreased overall survival for patients with NF1-MPNST (median OS of 17.9 months for aberrant expression and median OS not met (>120 months) for intact expression, p = 0.0276). In summary, we demonstrate that ATRX is aberrantly expressed in the majority of NF1-MPNSTs, but not plexiform or atypical neurofibromas. Additionally, aberrant ATRX expression is associated with decreased overall survival in NF1-MPNST, but not sporadic MPNST and may serve as a prognostic marker for patients with NF1-MPNST.
Highlights
Sarcomas are rare tumors that usually arise from bone or soft tissue
Of the patients from the Washington University cohort 11/21 Neurofibromatosis type 1 (NF1)-associated Malignant Peripheral Nerve Sheath Tumors (MPNSTs) clearly arose from a precursor plexiform or diffuse NF based on assessment of the pathologic specimen
One sporadic MPNST arose in an area of prior radiation treatment and none of the NF1-associated MPNSTs in either cohort arose in the area of prior radiation field (Table 1)
Summary
Sarcomas are rare tumors that usually arise from bone or soft tissue. Among soft tissue sarcomas, over 70 different subtypes exist. Almost half of malignant peripheral nerve sheath tumors (MPNSTs) occur sporadically (in the absence of a tumor predisposition syndrome) or as a complication of prior radiation therapy and the other half occur in the setting of the Neurofibromatosis type 1 (NF1) tumor predisposition syndrome [2] These tumors are thought to be composed of malignant cells with Schwannian differentiation, and in the setting of NF1 often arise from a benign precursor lesion, a plexiform neurofibroma (benign neurofibroma involving multiple fascicles of a peripheral nerve) or atypical neurofibromas (benign neurofibroma with cytologic atypia, increased cellularity, scattered mitotic figures, and/or loss of neurofibroma architecture, albeit with a low mitotic index of < 3/10 HPFs [3]). Prior genomic studies in our laboratory aimed at identifying potential therapeutic targets and biomarkers for MPNSTs had identified ATRX as a gene mutated in a subset of MPNSTs [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
