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.

Figure 1

Summary of mutations in study cohort. Mutations listed include only those expected to have pathogenic effect, either due to presence in a mutational hotspot or by an obvious gain of function/loss of function mechanism. Where indicated, patients were considered to have NF1 mutation based on clinical diagnosis alone (no clinical genetic testing data available). From top to bottom, grouping of findings includes: clinical information, mutation in previously reported recurrently altered genes in MPNST, additional Ras pathway activating mutations, and additional cell-cycle gene mutations.