Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Integrated analysis of genome-wide copy number and matched expression data reveals novel genes in esophageal adenocarcinoma

ABSTRACT: The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the west in the last 30 years and 5 year survival remains <14%. We aimed to characterize genome-wide aberrations in esophageal adenocarcinoma to further understand disease pathogenesis and ultimately identify groups with differential survivals with implications for clinical management. Oligo-array-based high-resolution analysis of copy number changes in 89 fresh frozen esophageal adenocarcinoma resection sections with long-term clinical follow-up data was performed. Good quality array comparative genomic hybridization profiles were obtained from 56/89 of the samples (63%). Our analyses confirmed known genomic aberrations in esophageal adenocarcinoma and identified 3 novel genomic regions with copy number changes. A modified T test with adjusted Bonferroni correction identified 17 genes with significantly different log2 ratios (p<4x10-7), including 6 novel genes, that characterize a group with a poorer survival. Total DNA isolated from human tissue sections was used to make fluorescently labeled DNA that was hybridized to Illumina HumanCytoSNP-12 Beadarray. All protocols were carried out following Illumina's standard protocols. After hybridization, raw data were recorded and normalized using Illumina's BeadStudio software v2.0. Matched expression data: GSE25201 GSE19417 D2 MRC/OEA0022CJ5 (GSM482819) D3 MRC/OEA0032CJ5 (GSM482817) D27 MRC/OEA0272CJ1 (GSM482814) D36 MRC/OEA0362CJ3 (GSM482806) D37 MRC/OEA0372AJ0 (GSM482800) D96 MRC/OEA0962BJ0 (GSM482847) D118 MRC/OEA1172CJ1 (GSM482848) D138 MRC/OEA1382CJ0 (GSM482844) D156 MRC/OEA1562CJ2 (GSM482853)

ORGANISM(S): Homo sapiens

SUBMITTER: Xin Yi Goh

PROVIDER: E-GEOD-25201 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma.

Goh X Y XY Rees J R E JR Paterson A L AL Chin S F SF Marioni J C JC Save V V O'Donovan M M Eijk P P PP Alderson D D Ylstra B B Caldas C C Fitzgerald R C RC

Gut 20110408 10

<h4>Background and aims</h4>The incidence of oesophageal adenocarcinoma (OAC) has been increasing rapidly with a dismal survival rate of less than 20%. Understanding the genomic aberrations and biology of this cancer may enhance disease interventions. This study aimed to use genome-wide genomic and expression data to enhance the understanding of OAC pathogenesis and identify groups with differential outcomes.<h4>Methods</h4>Array-comparative genomic hybridisation (aCGH) analysis was carried out ...[more]

PMID: 21478220

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Project description:The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the west in the last 30 years and 5 year survival remains <14%. We aimed to characterize genome-wide aberrations in esophageal adenocarcinoma to further understand disease pathogenesis and ultimately identify groups with differential survivals with implications for clinical management. Oligo-array-based high-resolution analysis of copy number changes in 89 fresh frozen esophageal adenocarcinoma resection sections with long-term clinical follow-up data was performed. Good quality array comparative genomic hybridization profiles were obtained from 56/89 of the samples (63%). Our analyses confirmed known genomic aberrations in esophageal adenocarcinoma and identified 3 novel genomic regions with copy number changes. A modified T test with adjusted Bonferroni correction identified 17 genes with significantly different log2 ratios (p<4x10-7), including 6 novel genes, that characterize a group with a poorer survival. Total RNA isolated from human tissue sections was used to make fluorescently labeled cRNA that was hybridized to DNA oligonucleotide. Briefly, 4 µg of total RNA was used to synthesize dsDNA through reverse transcription. cRNA was produced by in vitro transcription and labeled postsynthetically with Cy3 or Cy5. Two populations of labeled cRNA, a reference population and an experimental population, were compared with each other by competitive hybridization to microarrays. Two hybridizations were done with each cRNA sample pair using a fluorescent dye reversal strategy. Human microarrays contained oligonucleotide probes corresponding to approximately 21,000 genes. All oligonucleotide probes on the microarrays were synthesized in situ with inkjet technology (Agilent Technologies, Palo Alto, CA). After hybridization, arrays were scanned and fluorescence intensities for each probe were recorded. Ratios of transcript abundance (experimental to control) were obtained following normalization and correction of the array intensity data. Gene expression data analysis was done with the Rosetta Resolver gene expression analysis software (version 7.0, Rosetta Biosoftware, Seattle, WA).

Project description:Using data from high-density genomic profiling arrays, we describe the profiles of somatic copy-number aberrations (SCNAs) in 486 adenocarcinomas across all three major digestive organs, including 296 gastric and esophageal cancers. This analysis revealed that although patterns of broad, chromosome arm-level alterations are similar across the three types of adenocarcinoma, focal genomic amplifications are substantially more prevalent in gastric/esophageal adenocarcinoma. A statistical analysis identified 64 regions of significantly recurrent amplification and deletion, including those shared across these tumors and those uniquely significant in adenocarcinomas from a single organ. Among significantly amplified genes are those encoding therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, events noted in 14% of colorectal adenocarcinomas and 37% of gastric/esophageal tumors suggesting that analysis of genomic amplification will be a critical source of biomarkers to guide therapies in upper gastrointestinal adenocarcinomas. While many of the other significant loci of amplifications implicate genes recognized to play roles in gastrointestinal and other cancers, other loci point to regions that may harbor novel genes contributing to these cancers. One such event is a recurrent focal deletion present in 15% of esophageal adenocarcinomas, which we narrow to a single likely target, the Runt transcription factor subunit RUNX1. Indeed, reintroduction of RUNX1 into a cell model with this deletion inhibited anchorage-independent growth. Overall, these results demonstrate genomic features common to these tumors and identify key differences that reflect distinctive biology and potential opportunities for therapeutic intervention. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from 87 cancer DNAs derived from primary tumor tissues, as well as from DNA obtained from 1,480 normal DNA samples. Signal intensities were normalized to raw copy number estimates using the tangent normalization method, as described in Beroukhim et al., In Press and Mermel et al., In preparation. The 250K Sty data from this submission were combined with data for 128 colon adenocarcinomas (Firestein et al, Nature 2008) and segmented using GLAD. These segmented data were then combined with segmented SNP 6.0 data for 62 colon, 97 gastric and 112 esophageal adenocarcinomas using common markers to anchor the segments. Data analysis across samples was performed using this GISTIC 2.0 algorithm (Mermel C et al, Genome Biology 2011).

Project description:Using data from high-density genomic profiling arrays, we describe the profiles of somatic copy-number aberrations (SCNAs) in 486 adenocarcinomas across all three major digestive organs, including 296 gastric and esophageal cancers. This analysis revealed that although patterns of broad, chromosome arm-level alterations are similar across the three types of adenocarcinoma, focal genomic amplifications are substantially more prevalent in gastric/esophageal adenocarcinoma. A statistical analysis identified 64 regions of significantly recurrent amplification and deletion, including those shared across these tumors and those uniquely significant in adenocarcinomas from a single organ. Among significantly amplified genes are those encoding therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, events noted in 14% of colorectal adenocarcinomas and 37% of gastric/esophageal tumors suggesting that analysis of genomic amplification will be a critical source of biomarkers to guide therapies in upper gastrointestinal adenocarcinomas. While many of the other significant loci of amplifications implicate genes recognized to play roles in gastrointestinal and other cancers, other loci point to regions that may harbor novel genes contributing to these cancers. One such event is a recurrent focal deletion present in 15% of esophageal adenocarcinomas, which we narrow to a single likely target, the Runt transcription factor subunit RUNX1. Indeed, reintroduction of RUNX1 into a cell model with this deletion inhibited anchorage-independent growth. Overall, these results demonstrate genomic features common to these tumors and identify key differences that reflect distinctive biology and potential opportunities for therapeutic intervention. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from 271 cancer DNAs derived from primary tissues, as well as from DNA obtained from 60 normal DNA samples. Signal intensities were normalized to raw copy number estimates using the tangent normalization method, as described in Beroukhim et al., In Press and Mermel et al., In preparation. The SNP 6.0 data from this submission were segmented using CBS. These segmented data were then combined with segmented Affymetrix 250K Sty data for 128 colon, 13 gastric and 74 esophageal adenocarcinomas using common markers to anchor the segments. Data analysis across samples was performed using this GISTIC 2.0 algorithm (Mermel C et al, Genome Biology 2011).

Dataset Information

Integrated analysis of genome-wide copy number and matched expression data reveals novel genes in esophageal adenocarcinoma

Publications

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma.

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