Multiplatform Genomic Profiling and Immunohistochemistry Identify Prognostic and Predictive Signatures in Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

Purpose/Objective(s) Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms arising either sporadically or in patients with neurofibromatosis type 1 (NF1). To elucidate markers of prognosis and treatment response, we retrospectively identified MPNST tumor resection specimens at a single institution and performed histopathologic evaluation, immunohistochemistry (IHC), DNA methylation profiling, and whole exome sequencing (WES). Materials/Methods We identified a total of 54 consecutive patients treated at one institution between 1990 and 2019 with tumors meeting diagnostic criteria for MPNST and had sufficient tissue available for comprehensive histopathological evaluation (n = 54), DNA methylation profiling (n = 45) and whole exome sequencing (n = 35, n = 15 with paired normal). Overall survival (OS), metastasis free survival (MFS), and locoregional failure free rate (LFFR), were estimated using the Kaplan-Meier method. Log-rank test, Cox Proportional Hazards regression, and hierarchical clustering were performed in R. Results The median follow up was 22 months with no significant differences in LFFR, MFS, or OS between NF1 associated (n = 32) and sporadic MPNSTs (n = 22). Radiotherapy significantly improved LFFR (P = 0.05) but not OS. With regard to histopathologic and IHC analyses, increasing tumor grade using a two-tiered system (P = 0.01) and Ki-67 index (P = 0.01) were associated with worse OS. Unsupervised hierarchical clustering of DNA methylation profiles identified two groups with significant differences in chromosome instability and tumor purity but not clinical outcome. Recurrently identified copy number variants (CNVs) included chromosome 22q loss, 11q loss, 10 loss, 9p loss, 8q gain, and 1q loss. Chromosome 9p loss (P = 0.02) and 8q gain (P = 0.04) were significantly associated with worse OS. On WES analysis, recurrently mutated genes included NF1, EED, SUZ12, TP53, and CDKNA2A. Of these alterations, only CKND2A loss (on Chr9p) was associated with worse OS (P = 0.01). With regard to treatment response, MPNSTs exhibiting NF1 and H3K27 trimethylation loss demonstrated greater LFFR benefit from radiation therapy (P = 0.004) compared to NF1 and H3K27 trimethylation intact tumors (P = 0.83) with clinical NF1 diagnosis as the only significantly different baseline parameter between these two subgroups. Conclusion MPNSTs are a common cause of death in adult patients with NF1. Radiotherapy improves LFFR in all patients, and integrated IHC and genomic analysis further identifies putative prognostic and predictive markers, including the identification of a patient subset in whom the benefit of radiotherapy is most pronounced. Taken together, these data support radiation therapy in management of MPNSTs and suggest molecular characterization may be important for counseling patients with MPNST or potentially informing clinical trial design. Prospective and multi-institutional analyses are needed to validate these findings.