title: Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer.
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.
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McCleland
authors.affiliation: 1] Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA [2] Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Mayba
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.affiliation: 1] Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA [2] Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Durinck
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Ying-Jiun
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Hanbin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Chopra
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Murat B
authors.initials: MB
authors.lastname: Yaylaoglu
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.affiliation: Department of Non-clinical Biostatistics, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Houston N
authors.initials: HN
authors.lastname: Gilbert
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Reeder
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Pau
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.affiliation: Department of Discovery Oncology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020930:MAP Kinase Kinase Kinases; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
chemical_list: D020930:MAP Kinase Kinase Kinases; D020033:Protein Isoforms; D011494:Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C413047:MAP3K20 protein, human