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

Hirbe, Angela C.; Kaushal, Madhurima; Sharma, Mukesh Kumar; Dahiya, Sonika; Pekmezci, Melike; Perry, Arie; Gutmann, David H.

doi:10.1002/cncr.30455

Cited by 28 publications

(30 citation statements)

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“…TYK2, a member of the Janus Kinase family of proteins has been shown to play a role in immune surveillance and host response in the setting of infection, autoimmune disorders, and malignancy . More recent cancer genomic studies have identified activating mutations in TYK2 within cancer cells, implicating a cell intrinsic role for TYK2 in promoting cancer progression . Based on these genomic studies, we have begun to explore the role of TYK2 in MPNST pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25] More recent cancer genomic studies have identified activating mutations in TYK2 within cancer cells, implicating a cell intrinsic role for TYK2 in promoting cancer progression. 9,[25][26][27] Based on these genomic studies, we have begun to explore the role of TYK2 in MPNST pathogenesis. The current study raises several important points.…”

Section: Discussionmentioning

confidence: 99%

“…Prior work from our laboratory identified TYK2 as a gene mutated and frequently overexpressed in a subset of MPNSTs . Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK family), which includes three other members, JAK1‐3.…”

Section: Introductionmentioning

confidence: 99%

“…Prior work from our laboratory identified TYK2 as a gene mutated and frequently overexpressed in a subset of MPNSTs. 9 Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK family), 10 which includes three other members, JAK1-3. These proteins are non-receptor tyrosine kinases that are activated by auto or trans-phosphorylation after a cytokine binds to its respective receptor.…”

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TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death

et al. 2019

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Background Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 ( TYK2 ) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis. Methods Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout cells were established using shRNA and CRISPR/Cas9 systems, respectively. Results We have demonstrated that TYK2 was highly expressed in the majority of human MPNSTs examined. Additionally, we demonstrated that knockdown of Tyk2/TYK2 in murine and human MPNST cells significantly increased cell death in vitro. These effects were accompanied by a decrease in the levels of activated Stats and Bcl‐2 as well as an increase in the levels of Cleaved Caspase‐3. In addition, Tyk2 ‐KD cells demonstrated impaired growth in subcutaneous and metastasis models in vivo. Conclusion Taken together, these data illustrate the importance of TYK2 in MPNST pathogenesis and suggest that the TYK2 pathway may be a potential therapeutic target for these deadly cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death

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“…We evaluated the genetic fidelity of the PDX and cell line models by comparing mutational profiles of commonly mutated genes [14][15][16][17][18][19] from the exome-seq data to showcase that the mutational profiles between the original tumor were maintained in the cell lines and the PDX models, depicted in Figure 3a.…”

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confidence: 99%

A clinically and genomically annotated nerve sheath tumor biospecimen repository

Pollard

Banerjee

Doan

et al. 2019

Preprint

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Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at

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Multi‐Omics Profiling for NF1 Target Discovery in Neurofibromin (NF1) Deficient Cells

et al. 2019

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Loss of NF1 is an oncogenic driver. In efforts to define pathways responsible for the development of neurofibromas and other cancers, transcriptomic and proteomic changes are evaluated in a non-malignant NF1 null cell line. NF1 null HEK293 cells were created using CRISPR/Cas9 technology and they are compared to parental cells that express neurofibromin. A total of 1222 genes and 132 proteins are found to be differentially expressed. The analysis is integrated to identify eight transcripts/proteins that are differentially regulated in both analyses. Metacore Pathway analysis identifies Neurogenesis NGF/TrkA MAPK-mediated signaling alterations. Next, the data set is compared with other published studies that involve analysis of cells or tumors deficient for NF1 and it is found that 141 genes recur in the sample and others; only thirteen of these genes recur in two or more studies. Genes/proteins of interest are validated via q-RT-PCR or Western blot. It is shown that KRT8 and 14-3-3σ protein levels respond to exogenously introduced mNf1 cDNA. Hence, transcripts/proteins that respond to neurofibromin levels are identified and they can potentially be used as biomarkers.deletions, duplications, splicing variants, and rearrangements. Neurofibromin is best characterized by its ability to interact with and inactivate Ras through its GAP related domain (GRD). Hyperactivation of the Ras signaling pathway results in cellular over-proliferation and tumor formation. As such, NF1 is one of several disorders termed "Rasopathies," which also include Noonan syndrome, Costello syndrome, Legius syndrome, and others.Neurofibromin functions as a tumor suppressor. Inactivation of NF1 is sufficient for neurofibroma initiation. [1] Germline NF1 mutations have been associated with an earlier age of onset for breast cancer. Somatic mutations are present in tumors associated with NF1 and in a range of sporadic tumors in different cell types such as glioblastoma (up to 23%), lung adenocarcinoma (up to 11.8%), and breast cancer (reviewed in ref. 2). About 10-14% of children with juvenile myelomonocytic leukemia (JMML) have a clinical diagnosis of NF1 and NF1 mutations occur in approximately 30% of JMML cases. [3] This implies an important role for neurofibromin function in cancer development and progression.Since 2005, there have been at least fifteen studies utilizing sequencing, transcriptomics, and proteomics to discover factors important to NF1 pathology; these are summarized in Table S1, Supporting Information. [1,[4][5][6][7][8][9][10][11][12][13] One study looked only at whole exome sequencing, [10] two studies evaluated sequencing and transcriptomics, [1,8] nine were transcriptomic studies, [4,5,[11][12][13] two were proteomics studies with mouse tissues, [6,7] and one was a transcriptomic and proteomic study done after Nf1 siRNA treatment in rat cells. [9] These studies highlighted different drivers of NF1 pathology and took advantage of both mouse and human sources as well as a variety of cell types, including neurons, induced-n...

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

Cited by 28 publications

References 54 publications

TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death

TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death

A clinically and genomically annotated nerve sheath tumor biospecimen repository

Multi‐Omics Profiling for NF1 Target Discovery in Neurofibromin (NF1) Deficient Cells

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