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      Genomic analysis of atypical fibroxanthoma

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          Abstract

          Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.

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          Most cited references34

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          Oncotator: cancer variant annotation tool.

          Oncotator is a tool for annotating genomic point mutations and short nucleotide insertions/deletions (indels) with variant- and gene-centric information relevant to cancer researchers. This information is drawn from 14 different publicly available resources that have been pooled and indexed, and we provide an extensible framework to add additional data sources. Annotations linked to variants range from basic information, such as gene names and functional classification (e.g. missense), to cancer-specific data from resources such as the Catalogue of Somatic Mutations in Cancer (COSMIC), the Cancer Gene Census, and The Cancer Genome Atlas (TCGA). For local use, Oncotator is freely available as a python module hosted on Github (https://github.com/broadinstitute/oncotator). Furthermore, Oncotator is also available as a web service and web application at http://www.broadinstitute.org/oncotator/.
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            Mutational landscape of aggressive cutaneous squamous cell carcinoma.

            Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.
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              Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

              Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo, by normally binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis, and impacts patient survival. Together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings unify two outstanding questions in cancer biology: the basis of Wnt activation in non-colorectal tumors, and the identity of a 4q35 tumor suppressor.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administration
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: ResourcesRole: Supervision
                Role: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – original draft
                Role: VisualizationRole: Writing – original draft
                Role: Funding acquisitionRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 November 2017
                2017
                : 12
                : 11
                : e0188272
                Affiliations
                [1 ] Department of Dermatology, University of California, San Francisco, California, United States of America
                [2 ] Center for Cutaneous Research and Cell Biology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
                [3 ] Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom
                [4 ] Veterans Administration Medical Center, San Francisco, California, United States of America
                German Cancer Research Center (DKFZ), GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-5669-0627
                Article
                PONE-D-17-21062
                10.1371/journal.pone.0188272
                5687749
                29141020
                f4a047af-5011-40a3-93da-27d3a92d699d

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 1 June 2017
                : 3 November 2017
                Page count
                Figures: 5, Tables: 0, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000289, Cancer Research UK;
                Award Recipient :
                This work was funded by Cancer Research UK programme grant to Prof. Irene Leigh and UCSF Department of Dermatology funding to Dr Sarah Arron.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Fibroblasts
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Fibroblasts
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Fibroblasts
                Biology and life sciences
                Molecular biology
                Molecular biology techniques
                Sequencing techniques
                RNA sequencing
                Research and analysis methods
                Molecular biology techniques
                Sequencing techniques
                RNA sequencing
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Keratinocytes
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Keratinocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Keratinocytes
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Sarcomas
                Biology and Life Sciences
                Genetics
                Mutation
                Somatic Mutation
                Biology and Life Sciences
                Genetics
                Mutation
                Nonsense Mutation
                Biology and Life Sciences
                Genetics
                Gene Fusion
                Custom metadata
                Exome sequence data has been deposited to the SRA (Short Read Archive) database under SRP082197 and RNASeq data has been deposited to the GEO (Gene Expression Omnibus) database under GSE85671.

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