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

Jinfeng Liu (), Mark McCleland, Eric W. Stawiski, Florian Gnad, Oleg Mayba, Peter M. Haverty, Steffen Durinck, Ying-Jiun Chen, Christiaan Klijn, Suchit Jhunjhunwala, Michael Lawrence, Hanbin Liu, Yinan Wan, Vivek Chopra, Murat B. Yaylaoglu, Wenlin Yuan, Connie Ha, Houston N. Gilbert, Jens Reeder, Gregoire Pau, Jeremy Stinson, Howard M. Stern, Gerard Manning, Thomas D. Wu, Richard M. Neve, Frederic J. de Sauvage, Zora Modrusan, Somasekar Seshagiri, Ron Firestein () and Zemin Zhang ()
Additional contact information
Jinfeng Liu: Genentech Inc.
Mark McCleland: Genentech Inc.
Eric W. Stawiski: Genentech Inc.
Florian Gnad: Genentech Inc.
Oleg Mayba: Genentech Inc.
Peter M. Haverty: Genentech Inc.
Steffen Durinck: Genentech Inc.
Ying-Jiun Chen: Genentech Inc.
Christiaan Klijn: Genentech Inc.
Suchit Jhunjhunwala: Genentech Inc.
Michael Lawrence: Genentech Inc.
Hanbin Liu: Genentech Inc.
Yinan Wan: Genentech Inc.
Vivek Chopra: Genentech Inc.
Murat B. Yaylaoglu: Genentech Inc.
Wenlin Yuan: Genentech Inc.
Connie Ha: Genentech Inc.
Houston N. Gilbert: Genentech Inc.
Jens Reeder: Genentech Inc.
Gregoire Pau: Genentech Inc.
Jeremy Stinson: Genentech Inc.
Howard M. Stern: Genentech Inc.
Gerard Manning: Genentech Inc.
Thomas D. Wu: Genentech Inc.
Richard M. Neve: Genentech Inc.
Frederic J. de Sauvage: Genentech Inc.
Zora Modrusan: Genentech Inc.
Somasekar Seshagiri: Genentech Inc.
Ron Firestein: Genentech Inc.
Zemin Zhang: Genentech Inc.

Nature Communications, 2014, vol. 5, issue 1, 1-8

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4830

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