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High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH

ABSTRACT: Chromosomal regions harboring tumor suppressors and oncogenes are often deleted or amplified. Array comparative genomic hybridization (CGH) detects segmental DNA copy number alterations in tumor DNA relative to a normal control. The recent development of a bacterial artificial chromosome (BAC) array, that spans the human genome in a tiling path manner with >32,000 clones, has facilitated whole genome profiling at an unprecedented resolution. Using this technology, we comprehensively describe and compare the genomes of 28 commonly used non-small cell lung carcinoma cell models, derived from 18 adenocarcinomas, 9 squamous cell carcinomas, and 1 large cell carcinoma. Analysis at such resolution not only provided a detailed genomic alteration template for each of these model cell lines, but revealed novel regions of frequent duplication and deletion. Significantly, a detailed analysis of chromosome 7 identified 6 distinct regions of alterations across this chromosome implicating the presence of multiple novel oncogene loci on this chromosome. As well, a comparison between the squamous and adenocarcinoma cells revealed alterations common to both subtypes, such as the loss of 3p and gain of 5p, in addition to multiple hotspots more frequently associated with only one subtype. Interestingly, chromosome 3q, which is known to be amplified in both subtypes, showed two distinct regions of alteration, one frequently altered in squamous and one more frequent altered in adenocarcinoma. In summary, our data demonstrates the unique information generated by high resolution analysis of NSCLC genomes and uncovers the presence of genetic alterations prevalent in the different NSCLC subtypes. Keywords: array CGH, amplification, segmental copy number, NSCLC, Lung cancer, genetic alterations

ORGANISM(S): Homo sapiens

PROVIDER: GSE2922 | GEO | 2006/02/21

SECONDARY ACCESSION(S): PRJNA92611

REPOSITORIES: GEO

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Project description:BACKGROUND: Cervical carcinoma develops as a result of multiple genetic alterations. Different studies investigated genomic alterations in cervical cancer mainly by means of metaphase comparative genomic hybridization (mCGH) and microsatellite marker analysis for the detection of loss of heterozygosity (LOH). Currently, high throughput methods such as array comparative genomic hybridization (array CGH), single nucleotide polymorphism array (SNP array) and gene expression arrays are available to study genome-wide alterations. Integration of these 3 platforms allows detection of genomic alterations at high resolution and investigation of an association between copy number changes and expression. RESULTS: Genome-wide copy number and genotype analysis of 10 cervical cancer cell lines by array CGH and SNP array showed highly complex large-scale alterations. A comparison between array CGH and SNP array revealed that the overall concordance in detection of the same areas with copy number alterations (CNA) was above 90%. The use of SNP arrays demonstrated that about 75% of LOH events would not have been found by methods which screen for copy number changes, such as array CGH, since these were LOH events without CNA. Regions frequently targeted by CNA, as determined by array CGH, such as amplification of 5p and 20q, and loss of 8p were confirmed by fluorescent in situ hybridization (FISH). Genome-wide, we did not find a correlation between copy-number and gene expression. At chromosome arm 5p however, 22% of the genes were significantly upregulated in cell lines with amplifications as compared to cell lines without amplifications, as measured by gene expression arrays. For 3 genes, SKP2, ANKH and TRIO, expression differences were confirmed by quantitative real-time PCR (qRT-PCR). CONCLUSION: This study showed that copy number data retrieved from either array CGH or SNP array are comparable and that the integration of genome-wide LOH, copy number and gene expression is useful for the identification of gene specific targets that could be relevant for the development and progression in cervical cancer. Keywords: DNA copynumber RNA expression correlation

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High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH

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