Show simple item record

dc.contributor.authorHudson, Andrew M
dc.contributor.authorStephenson, Natalie L
dc.contributor.authorLi, Cynthia
dc.contributor.authorTrotter, Eleanor W
dc.contributor.authorFletcher, Adam J
dc.contributor.authorKatona, Gitta
dc.contributor.authorBieniasz-Krzywiec, Patrycja
dc.contributor.authorHowell, Matthew
dc.contributor.authorWirth, Christopher
dc.contributor.authorFurney, S
dc.contributor.authorMiller, Crispin J
dc.contributor.authorBrognard, John
dc.date.accessioned2018-06-30T14:05:22Z
dc.date.available2018-06-30T14:05:22Z
dc.date.issued2018-04-17
dc.identifier.citationTruncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases. 2018, 11(526): Sci Signalen
dc.identifier.issn1937-9145
dc.identifier.pmid29666306
dc.identifier.doi10.1126/scisignal.aan6776
dc.identifier.urihttp://hdl.handle.net/10541/621076
dc.description.abstractA 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.
dc.language.isoenen
dc.rightsArchived with thanks to Science signalingen
dc.titleTruncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.en
dc.typeArticleen
dc.contributor.departmentSignalling Networks in Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BXen
dc.identifier.journalScience Signalingen
refterms.dateFOA2020-04-27T11:12:02Z
html.description.abstractA 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.


Files in this item

Thumbnail
Name:
560415.pdf
Size:
2.138Mb
Format:
PDF
Description:
From UNPAYWALL

This item appears in the following Collection(s)

Show simple item record