The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma. To more fully characterize the genomic landscape of this tumor type, we performed next generation sequencing studies for mutational and copy number analysis. We analyzed whole exome sequencing data from 12 MPNST and SNP arrays for a subset of these. We additionally conducted a literature review of prior next generation sequencing studies in this disease and compared to the current study. We report recurrent mutations in NF1, SUZ12, EED, TP53 and CDKN2A in our study cohort. Combined with prior studies, we calculate the disease specific incidence of mutation in these genes to be: NF1 (56/64 = 87.5%). SUZ12 (69/123 = 56.1%), EED (40/123 = 32.5%), TP53 (29/72 = 40.3%), and CDKN2A (54/72 = 75.0%). Notably, we also identified frequent Ras pathway activating somatic mutations outside of these previously reported recurrently mutated genes. Five of the 12 MPNST in our cohort (42%) contained such a mutation. In conclusion, our study adds to the growing understanding of the genomic complexity of MPNST. We report a previously underappreciated frequency and variety of secondary or tertiary Ras pathway activating mutations, though not highly recurrent in a single gene.

Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK

“…Given that TP53, RB, and ATM are central regulators of the cell cycle, the genetic status of these tumor suppressors may influence sensitivity to DUSP inhibitors. The incidence of mutation of TP53 is 40% in MPNSTs (44). In MPNSTs with WT TP53, DUSP inhibition with acute reactivation of JNK signaling appears to stabilize TP53, enabling the apoptotic pathway as occurs in other settings (34,35).…”

Mechanisms underlying synergy between DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors in NF1-associated malignant peripheral nerve sheath tumors

“…We have generated an nf1 mutant zebrafish model and shown that the combination of nf1 loss and tp53 deficiency promotes a higher penetrance and much more rapid onset of MPNSTs than is observed in the absence of nf1 alone [20,21]. Brohl et al [22] reported the results of nextgeneration sequencing of MPNSTs combined with a literature survey of >64 human MPNST tumor samples. In that study, mutation frequencies of NF1 and TP53 were 87.5% and 40.3%, respectively, indicating the relevance of our zebrafish model with NF1-and tp53-inactivating mutations [22].…”

“…Brohl et al [22] reported the results of nextgeneration sequencing of MPNSTs combined with a literature survey of >64 human MPNST tumor samples. In that study, mutation frequencies of NF1 and TP53 were 87.5% and 40.3%, respectively, indicating the relevance of our zebrafish model with NF1-and tp53-inactivating mutations [22]. Moreover, the histologic features of the MPNSTs in zebrafish are very similar to those of the human tumors [15,20].…”

Malignant peripheral nerve sheath tumor: Transformation in a patient with neurofibromatosis type 2

“…Approximately half of all MPNSTs are associated with germline NF1 mutations, and many sporadic MPNSTs carry acquired NF1 mutations. Other genes that have been associated with the development of MPNST include cell‐cycle regulators CDK2NA/p16, TP53, RB1 , elements of histone methyltransferase PRC2, SUZ12 , and EED , and schwannomatosis‐associated tumor suppressor gene SMARCB1 mutations . No mutations in any of these were identified in our patient's MPNST.…”

“…Interestingly, the transformation described here seems to have followed the transformation process common to NF1 patients, as described by Miettinen et al 8 tumor suppressor gene SMARCB1 mutations. [9][10][11][12] No mutations in any of these were identified in our patient's MPNST. Prior to malignant transformation, NGS revealed the germline NF2 frameshift mutation, a missense mutation in EGFR, and VUS of MAPK.…”