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    Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers.

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    Laminin-binding integrin gene ...
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    Author
    Harryman, William L
    Pond, Erika
    Singh, Parminder
    Little, Andrew S
    Eschbacher, Jennifer M
    Nagle, Raymond B
    Cress, Anne E
    Affiliation
    The University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, Arizona, United States
    Issue Date
    2016-01-01
    Keywords
    Cancer
    cBioPortal
    copy number alterations
    gene copy
    integrin
    laminin
    
    Metadata
    Show full item record
    Publisher
    e-Century Publishing
    Citation
    Harryman WL, Pond E, Singh P, Little AS, Eschbacher JM, Nagle RB, Cress AE. Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers. American journal of translational research. 2016;8(2):940.
    Journal
    American journal of translational research
    Rights
    AJTR Copyright © 2016.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    The laminin-binding integrin (LBI) family are cell adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. We investigated whether copy number alteration (CNA) or mutations of a five-gene signature (ITGB4, ITGA3, LAMB3, PLEC, and SYNE3), representing essential genes for LBI adhesion, would correlate with patient outcomes within human epithelial-type tumor data sets currently available in an open access format. We investigated the relative alteration frequency of an LBI signature panel (integrin β4 (ITGB4), integrin α3 (ITGA3), laminin β3 chain (LAMB3), plectin (PLEC), and nesprin 3 (SYNE3)), independent of the epithelial cancer type, within publically available and published data using cBioPortal and Oncomine software. We rank ordered the results using a 20% alteration frequency cut-off and limited the analysis to studies containing at least 100 samples. Kaplan-Meier survival curves were analyzed to determine if alterations in the LBI signature correlated with patient survival. The Oncomine data mining tool was used to compare the heat map expression of the LBI signature without SYNE3 (as this was not included in the Oncomine database) to drug resistance patterns. Twelve different cancer types, representing 5,647 samples, contained at least a 20% alteration frequency of the five-gene LBI signature. The frequency of alteration ranged from 38.3% to 19.8%. Within the LBI signature, PLEC was the most commonly altered followed by LAMB3, ITGB4, ITGA3, and SYNE3 across all twelve cancer types. Within cancer types, there was little overlap of the individual amplified genes from each sample, suggesting different specific amplicons may alter the LBI adhesion structures. Of the twelve cancer types, overall survival was altered by CNA presence in bladder urothelial carcinoma (p=0.0143*) and cervical squamous cell carcinoma and endocervical adenocarcinoma (p=0.0432*). Querying the in vitro drug resistance profiles with the LBI signature demonstrated a positive correlation with cells resistant to inhibitors of HDAC (Vorinostat, Panobinostat) and topoisomerase II (Irinotecan). No correlation was found with the following agents: Bleomycin, Doxorubicin, Methotrexate, Gemcitabine, Docetaxel, Bortezomib, and Shikonen. Our work has identified epithelial-types of human cancer that have significant CNA in our selected five-gene signature, which was based on the essential and genetically-defined functions of the protein product networks (in this case, the LBI axis). CNA of the gene signature not only predicted overall survival in bladder, cervical, and endocervical adenocarcinoma but also response to chemotherapy. This work suggests that future studies designed to optimize the gene signature are warranted.
    Note
    Open access journal.
    ISSN
    1943-8141
    PubMed ID
    27158381
    Version
    Final published version
    Sponsors
    The use of the Tissue Acquisition and Molecular Analysis Support Service (TACMASR) of the UA Cancer Center was essential for this work. Of particular note was the expert technical assistance of Ed Abril. The work was supported in part by CA P30 23074, CA164484 and CA159406.
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