Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1‐associated malignant peripheral nerve sheath tumors

BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1‐associated MPNSTs (NF1‐MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1‐MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy. METHODS Clinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1‐MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations. RESULTS A total of 3 women and 4 men with NF1‐MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [ NF1 ], ROS proto‐oncogene 1 [ ROS1 ], tumor protein p53 [ TP53 ], and tyrosine kinase 2 [ TYK2 ]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%‐35%), another neural crest‐derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (<7%). In the current series, recurrent TYK2 mutations were identified in 2 cases of NF1‐MPNST (30% of cases), whereas TYK2 protein overexpression was observed in 60% of MPNST cases using an independently generated tissue microarray, regardless of NF1 status. CONCLUSIONS Clinical genomic analysis of the current series of NF1‐MPNST cases found that TYK2 is a new gene mutated in MPNST. Future work will focus on examining the utility of TYK2 expression as a biomarker and therapeutic target for these cancers. Cancer 2017;123:1194–1201. © 2016 American Cancer Society .