Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma

Nicholas J. Wang, Zachary Sanborn, Kelly L. Arnett, Laura J. Bayston, Wilson Liao, Charlotte M. Proby, Irene M. Leigh, Eric A. Collisson, Patricia B. Gordon, Lakshmi Jakkula, Sally Pennypacker, Yong Zou, Mimansa Sharma, Jeffrey P. North, Swapna S. Vemula, Theodora M. Mauro, Isaac M. Neuhaus, Philip E. LeBoit, Joe S. Hur, Kyunghee ParkNam Huh, Pui-Yan Kwok, Sarah T. Arron, Pierre P. Massion, Allen E. Bale, David Haussler, James E. Cleaver, Joe W. Gray, Paul T. Spellman, Andrew P. South, Jon C. Aster, Stephen C. Blacklow, Raymond J. Cho

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    278 Citations (Scopus)

    Abstract

    Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in similar to 75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

    Original languageEnglish
    Pages (from-to)17761-17766
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Issue number43
    DOIs
    Publication statusPublished - 25 Oct 2011

    Keywords

    • cancer genetics
    • genomic
    • cellular signaling
    • CHRONIC LYMPHOCYTIC-LEUKEMIA
    • ACUTE LYMPHOBLASTIC-LEUKEMIA
    • GROWTH-FACTOR RECEPTOR
    • DROSOPHILA NOTCH
    • LIGAND-BINDING
    • C-MYC
    • SKIN
    • GENE
    • HEAD
    • NECK

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