Research ArticleCancer

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

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Sci. Signal.  17 Apr 2018:
Vol. 11, Issue 526, eaan6776
DOI: 10.1126/scisignal.aan6776

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Sorting through the noise

Genomic sequencing has been a boon to understanding, diagnosing, and treating cancer and other diseases, but it can be difficult to sort the “driver” mutations from natural variants and silent mutations, particularly in such heterogeneous samples as tumors. Hudson et al. used a combination of bioinformatics, structural modeling, and biochemistry to identify loss-of-function, driver mutations in kinases that as yet have been lost in the noise of sequencing data in the TCGA and CCLE databases. By focusing their analysis on the sequences surrounding the generally conserved catalytic domain, the authors identified a broadly tumor-suppressive kinome, which revealed critical loss-of-function mutations in the kinase MAP2K7 in stomach cancers. Restoring mutant gastric cancer cells with a functional kinase reduced their growth in culture models, indicating an avenue to explore further for clinical benefit.

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.

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