Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer

Nat Commun. 2014 May 8:5:3830. doi: 10.1038/ncomms4830.


Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumours and 32 cell lines. Meta-analysis of exome data and previously published data sets reveals 24 significantly mutated genes in microsatellite stable (MSS) tumours and 16 in microsatellite instable (MSI) tumours. Over half the patients in our collection could potentially benefit from targeted therapies. We identify 55 splice site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumours. ZAK kinase isoform TV1 is preferentially upregulated in gastric tumours and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder and breast cancers. Overexpression of this particular isoform activates multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibits proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.

MeSH terms

  • Base Sequence
  • Cell Line
  • Cell Proliferation / genetics
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Humans
  • MAP Kinase Kinase Kinases
  • Microsatellite Instability
  • Microsatellite Repeats / genetics
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Protein Isoforms / genetics*
  • Protein Kinases / genetics*
  • Receptor, ErbB-2 / genetics
  • Sequence Analysis, DNA
  • Stomach Neoplasms / genetics*
  • Transcriptome / genetics


  • Protein Isoforms
  • Protein Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • MAP Kinase Kinase Kinases
  • MAP3K20 protein, human