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      Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma

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          Abstract

          Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors.

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          N. Agrawal, M Frederick, C. R. Pickering … (2011)
          Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
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            Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers.

            Curtis R. Pickering, Jiexin Zhang, Suk Young Yoo … (2013)
            The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.
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              mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling.

              Audrey Carrière, Sébastien Moreau, Louis-André Julien … (2010)
              The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. While mTOR complex 1 (mTORC1) regulates mRNA translation and ribosome biogenesis, mTORC2 plays an important role in the phosphorylation and subsequent activation of Akt. Interestingly, mTORC1 negatively regulates Akt activation, but whether mTORC1 signaling directly targets mTORC2 remains unknown. Here we show that growth factors promote the phosphorylation of Rictor (rapamycin-insensitive companion of mTOR), an essential subunit of mTORC2. We found that Rictor phosphorylation requires mTORC1 activity and, more specifically, the p70 ribosomal S6 kinase 1 (S6K1). We identified several phosphorylation sites in Rictor and found that Thr1135 is directly phosphorylated by S6K1 in vitro and in vivo, in a rapamycin-sensitive manner. Phosphorylation of Rictor on Thr1135 did not affect mTORC2 assembly, kinase activity, or cellular localization. However, cells expressing a Rictor T1135A mutant were found to have increased mTORC2-dependent phosphorylation of Akt. In addition, phosphorylation of the Akt substrates FoxO1/3a and glycogen synthase kinase 3 alpha/beta (GSK3 alpha/beta) was found to be increased in these cells, indicating that S6K1-mediated phosphorylation of Rictor inhibits mTORC2 and Akt signaling. Together, our results uncover a new regulatory link between the two mTOR complexes, whereby Rictor integrates mTORC1-dependent signaling.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 11 July 2017
                Publication date (Electronic): 29 April 2017
                Volume: 8
                Issue: 28
                Pages: 46065-46070
                Affiliations
                1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
                2 Department of Pediatrics, Division of Pediatric Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA
                3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
                4 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
                5 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
                6 Body and Nuclear Radiology Sections, Texas Children's Hospital, Houston, TX 77030, USA
                7 Center for Cell and Gene Therapy, Houston, TX 77030, USA
                8 Department of Oncological Sciences, Icahn School of Medicine, New York, NY 10029, USA
                9 Tisch Cancer Institute, Icahn School of Medicine, New York, NY 10029, USA
                10 Immunology Institute, Icahn School of Medicine, New York, NY 10029, USA
                11 Department of Dermatology, Icahn School of Medicine, New York, NY 10029, USA
                Author notes
                Correspondence to: Donald W. Parsons, dwparson@ 123456txch.org
                Carl E. Allen, ceallen@ 123456txch.org
                Article
                Publisher ID: 17521
                DOI: 10.18632/oncotarget.17521
                PMC ID: 5542249
                PubMed ID: 28512266
                SO-VID: d144facf-fd96-4586-99c0-7c385cf3e588
                Copyright © Copyright: © 2017 Chakraborty et al.
                License:

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 13 October 2016
                Date accepted : 13 March 2017
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: juvenile xanthogranuloma,mapk1,erk activation,histiocytic disorder,somatic mutation
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: juvenile xanthogranuloma, mapk1, erk activation, histiocytic disorder, somatic mutation

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