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    Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.

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    Authors
    Hudson, Andrew M
    Stephenson, Natalie L
    Li, Cynthia
    Trotter, Eleanor W
    Fletcher, Adam J
    Katona, Gitta
    Bieniasz-Krzywiec, Patrycja
    Howell, Matthew
    Wirth, Christopher
    Furney, S
    Miller, Crispin J
    Brognard, John
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    Affiliation
    Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX
    Issue Date
    2018-04-17
    
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    Abstract
    A major challenge in cancer genomics is identifying "driver" mutations from the many neutral "passenger" mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer.
    Citation
    Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases. 2018, 11(526): Sci Signal
    Journal
    Science Signaling
    URI
    http://hdl.handle.net/10541/621076
    DOI
    10.1126/scisignal.aan6776
    PubMed ID
    29666306
    Type
    Article
    Language
    en
    ISSN
    1937-9145
    ae974a485f413a2113503eed53cd6c53
    10.1126/scisignal.aan6776
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