Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genetic Landscape of Copy Number Alterations in Gastric Cancer

ABSTRACT: Genome-wide DNA copy number profiling of gastric tumors and matched non-maligant samples. The affymetrix SNP6 array was used to obtain DNA copy number profiles in 193 gastric tumors and 98 matched gastric non-malignant samples. Genomic DNA extracted from 193 gastric tumors and 98 matched gastric non-malignant (normal) tissues was hybridized on Affymetrix SNP6 genotyping arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Niantao Deng

PROVIDER: E-GEOD-31168 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.

Deng Niantao N Goh Liang Kee LK Wang Hannah H Das Kakoli K Tao Jiong J Tan Iain Beehuat IB Zhang Shenli S Lee Minghui M Wu Jeanie J Lim Kiat Hon KH Lei Zhengdeng Z Goh Glenn G Lim Qing-Yan QY Tan Angie Lay-Keng AL Sin Poh Dianne Yu DY Riahi Sudep S Bell Sandra S Shi Michael M MM Linnartz Ronald R Zhu Feng F Yeoh Khay Guan KG Toh Han Chong HC Yong Wei Peng WP Cheong Hyun Cheol HC Rha Sun Young SY Boussioutas Alex A Grabsch Heike H Rozen Steve S Tan Patrick P

Gut 20120207 5

<h4>Objective</h4>Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers.<h4>Design</h4>Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled ...[more]

PMID: 22315472

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Project description:Background & Aims: E-cadherin expression disruption is commonly observed in epithelial cancers and metastasis. Such event is also recognized as a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression and function of pivotal cancer-related genes, we characterized and dissected a pathway initiated by loss of microRNA-101 that causes E-cadherin dysfunction through upregulation of EZH2 expression in GC. Methods: Microarrays were used to profile the expression of microRNAs in human GC. Array-CGH revealed DNA copy number changes that were validated by genomic quantitative PCR and Snapshot. Expression levels of microRNAs, mRNA and protein were determined by quantitative-real time PCR and western-blot/co-immunofluorescence. CDH1 inactivating mechanisms were analyzed. Gain and loss of function experiments were done in KatoIII cells. E-cadherin functionality was assessed by immunofluorescence and flow cytometry. Results: MiR-101 expression was significantly decreased in tumors in comparison with normal gastric mucosas (P<.0001). In 65% of the analyzed GC cases, miR-101 downregulation was caused by deletions and/or microdeletions at miR-101-2 locus. EZH2 overexpression and consequent loss/aberrant E-cadherin expression was found in concomitance with miR-101 downregulation in 41% of the analyzed GC cases. This occurred preferentially in cases retaining allele(s) untargeted by classical CDH1 inactivating mechanisms. MiR-101 gain of function experiments or direct inhibition of EZH2, led to a strong depletion of endogenous EZH2 protein and consequent rescue of functional E-cadherin at the cell membrane, mimicking results obtained with clinical GC samples. Conclusions: Deletions and/or microdeletions at miR-101-2 locus underlying mature miR-101 downregulation and consequent EZH2 overexpression represented a novel cascade of genetic events leading to E-cadherin disruption, preferentially affecting the intestinal-type of GC. In the present study, 37 primary GCs and a pool of 10 normal gastric mucosas were used to acquire the expression of 703 known human mature miRNAs deposited in the Sanger miRBase Sequence Database, Release 10.0 (http://microrna.sanger.ac.uk), as well as 393 novel human miRNAs discovered through deep sequencing and validated by qRT-PCR and array profiling (NCodeM-bM-^DM-" Human miRNA microarray probe set V3 from Invitrogen). The 10 normal gastric mucosa RNA samples were pooled to obtain the normal gastric reference sample, which was labelled and hybridised four times to check arrays' reproducibility.

Dataset Information

Genetic Landscape of Copy Number Alterations in Gastric Cancer

Publications

A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.

Similar Datasets

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