EGAGenomicsIllumina HiSeq 2000, unknownOtherhttps://ega-archive.org/studies/EGAS00001000736EGAEGA study EGAS00001000736Title not providedGenentech gastric tumor sequencingrestrictedEGAGastric 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.Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer.Liu Jinfeng J, McCleland Mark M, Stawiski Eric W EW, Gnad Florian F, Mayba Oleg O, Haverty Peter M PM, Durinck Steffen S, Chen Ying-Jiun YJ, Klijn Christiaan C, Jhunjhunwala Suchit S, Lawrence Michael M, Liu Hanbin H, Wan Yinan Y, Chopra Vivek V, Yaylaoglu Murat B MB, Yuan Wenlin W, Ha Connie C, Gilbert Houston N HN, Reeder Jens J, Pau Gregoire G, Stinson Jeremy J, Stern Howard M HM, Manning Gerard G, Wu Thomas D TD, Neve Richard M RM, de Sauvage Frederic J FJ, Modrusan Zora Z, Seshagiri Somasekar S, Firestein Ron R, Zhang Zemin ZStomach Cancer, whole exome, tumour of stomach, gastric tumour, stomach neoplasm (disease), Neoplasms, stomach tumour, Exomes, Gastric Cancers, Cell Lines, RNA-seq, Cancers, Gastric Cancer, neoplasm of the stomach, Gastric Neoplasm, Stomach Neoplasms, gastric tumor, Cell, STOMACH NEOPL, NEOPL STOMACH, Stomach, Stomach Cancers, stomach neoplasm, neoplasm of stomach, Cancer of Stomach, NEOPL GASTRIC, tumor of stomach, Neoplasm, Line, Whole Transcriptome Shotgun Sequencing, Cell., Gastric Neoplasms, Cancer of the Stomach, tumor of the stomach, gastric neoplasm, Gastric, tumour of the stomach, stomach tumor, Cancer, GASTRIC NEOPL, LinesMLK7., T-cell leukemia, Zak, Breasts, Materials, AGL4, Gene Expression Profile, Lactiferous gland, Profiles, Tumor, Stomach Neoplasms, glandula mammaria, malignant fundus of stomach neoplasm, NEOPL STOMACH, Case Fatality Rates, Mutations, Death Rates, malignant neoplasm of fundus of stomach, Familial Diffuse, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, Line, Excess Mortalities, Kinase, tumor of the stomach, gastric fundus cancer, gastric neoplasm, average, Crude Mortality Rates, F10N7_150, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, Signatures, malignant neoplasm of body of stomach, malignant neoplasm, Expression Signature, malignant tumour of fundus of stomach, CFR Case Fatality Rate, Transcriptomes, AGAMOUS-like 4, MLTK, s, Urinary, Malignancies, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, Cancer of the Stomach, Age-Specific Death Rate, ATP Phosphotransferases, Ca body - 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stomach, ATP, TRANSCRIPTION FACTOR, Tumors, RNA polymerase II distal enhancer sequence-specific binding, mamma, RNA polymerase II core promoter proximal region sequence-specific binding, aberrant, GASC, Expression Profiles, Crude Death, MLT, neoplastic disease, neoplasm of the stomach, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, tumours, results, STOMACH NEOPL, Crude Mortality, Gene Expression, Mortality, Benign, Expression Signatures, Lobe of mammary gland, vesica urinaria, Genetic Materials, Gastric Neoplasms, Detrusor Muscles, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, MLTKalpha, Expression Profile, Genetic Material, region, Transcriptome Profiles, Lines, Stomach Cancer, F14P3.4, Transphosphorylases, Marinesco-Sjögren syndrome, Factors, gastric tumour, death rate, stomach neoplasm (disease), Exomes, F14P3_4, Benign Neoplasms, Mortalities, Transcription factor, Detrusor Muscle, Malignant Neoplasms, Stomach, Mortality Rate, Crude Death Rate, Patient, Material, neoplasm of stomach, Proliferation, Marinesco-Sjogren-Garland syndrome, tumor of stomach, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, Cistron, Mortality Determinant, bladder, other neoplasm, metal ion regulated sequence-specific DNA binding, ca greater curvature of stomach, metal ion regulated proximal promoter sequence-specific DNA binding, Proliferating, Detrusor Urinae, mammary region, whole exome, atypia, nuclear mRNA cis splicing, Transcriptome Profile, Mortality Declines, Neoplasms, B230120H23Rik, MLK7, Benign Neoplasm, Excess, Gene, Crude Mortality Rate, SEPALLATA 2, Malignant, mortality measurement, Transcription Factor, NEOPL, Age-Specific Death, Mortality Determinants, Crude, Rate, Determinant, zinc ion regulated core promoter proximal region sequence-specific DNA binding, Ca fundus - stomach, stomach neoplasm, Case Fatality, AZK, malignant tumor of fundus of stomach, atypical, neoplasm, Phosphotransferase, stomach tumor, Differential Mortality, vesica, Transcription, Excess Mortality, MRK, Genetic, pattern, Malignancy, distribution, Profile, mlklak, proliferating, stomach tumour, mammary part of chest, tumour, Gastric Cancer, Transphosphorylase, Age-Specific, Neoplasias, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), gastric cancer, via U2-type spliceosome, RNA polymerase II proximal promoter sequence-specific DNA binding, Cancer of Stomach, MSS, Clients, copper ion regulated proximal promoter sequence-specific DNA binding, Mortality Rates, mortality rate, Crude Death Rates, site, Age Specific Death Rate, Neoplastic Growth, Cancer, ULG5, tumour of stomach, Stomach Neoplasm, Transcriptome, Malignant Neoplasm, Mortality Decline, Cell Lines, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, defective, Factor, fundus of stomach cancer, Cistrons, Brustdruese, cancer of fundus of stomach, Client, Gastric cancer, gastric tumor, Cell, Phosphotransferases, Stomach Cancers, transcription factor activity, Case Fatality Rate, Marinesco-Sjogren syndrome-Hypergonadotrophic hypogonadism, neoplastic growth, MT, survival, Bladder Detrusor Muscles, Gene Expression Signatures, Neoplasm, RNA polymerase II transcription factor activity, Gene Expression Signature, Determinants, Death, Gastric, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, Rates, Death Rate, primary cancer, urocyst, Bladder, Kinases, Lobe of breast, Gastric Cancers, Cancers, Age-Specific Death Rates, metal ion regulated core promoter proximal region sequence-specific binding, copper ion regulated core promoter proximal region sequence-specific binding, Gastric Neoplasm, disease of cellular proliferation, malignant tumor, F10N7.150, Marinesco-Sjogren syndrome-myopathy, Differential, AV006891, Gene Expression Profiles, NEOPL GASTRIC, Decline, BAP, Signature, tumour of the stomach, pk, Neoplasia, NEOPLASMS BENIGN, MLTKbeta, Differential Mortalities, breast, GASTRIC NEOPL, Bladder Detrusor MusclefalseExome-seq, RNA-Seq, SNP array profiling of gastric tumor samples and cell lines.Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we performed exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumors and 32 cell lines. Meta-analysis of the exome data and previously published data sets revealed 24 significantly mutated genes in MSS tumors, and 16 in MSI tumors. More than half of the patients in our collection could potentially benefit from targeted therapies. We identified 55 splice-site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumors. The ZAK kinase isoform TV1 is preferentially upregulated in gastric tumors and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder, and breast cancers. Overexpression of this particular isoform activated multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibited proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.2019-10-31 12:52:11EGAS00001000736960624807215EGAD00010000622EGAD00001000815EGAC00001000055