title: Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Hirbe
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Kaushal
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Mukesh Kumar
authors.initials: MK
authors.lastname: Sharma
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.affiliation: Department of Pathology, University of California at San Francisco School of Medicine, San Francisco, California.
authors.forename: Melike
authors.initials: M
authors.lastname: Pekmezci
authors.affiliation: Department of Pathology, University of California at San Francisco School of Medicine, San Francisco, California.|Department of Neurological Surgery, University of California at San Francisco School of Medicine, San Francisco, California.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Neurology, Washington University, St. Louis, Missouri.
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D000090063:Proto-Oncogene Mas; D053634:TYK2 Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D053634:TYK2 Kinase
keywords: ROS proto-oncogene 1 (ROS1); cancer predisposition; neurofibromatosis; sarcoma; tyrosine kinase 2 (TYK2)