Unknown,Transcriptomics,Genomics,Proteomics

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An integrated genomics approach for novel biomarker discovery in squamous cell cervical carcinoma

ABSTRACT: Detection of copy number dependent gene expression profiles in epithelial tumours has lead to the discovery of genes significant in diagnosis, prognosis and of therapeutic value. We sought to apply the technologies of gene expression profiling and copy number aberration detection by high density oligonucleotide microarray analysis to detect genes with expression profiles regulated by copy number. We surveyed copy number aberrations in 27 squamous cell carcinomas tissues and ten cervical carcinoma cell lines by Agilent 244k aCGH, and in a companion study of 77 tissues we obtained transcriptional profiles of a broader ranger of histologies. Briefly, for normal (NAD) and squamous intraepithelial lesions (SILs), DNA and RNA were extracted from approximately 5 - 25 x 5 mm thin sections of fresh frozen cervical tissue, respectively. Epithelial were microdissected, pooled and processed as follows. For RNA extraction, tissue was collected in Trizol (Invitrogen, UK) and subject to homogenization (Polytron), total RNA was recovered following standard processes, and quality assessed by BioAnalyzer (Agilent). DNA was recovered following Proteinase K digestion, phenol chloroform extraction, and ethanol precipitation. Contaminating RNA was removed by RNAse A treatment, and a second round of phenol chloroform extraction and ethanol precipitation. For SCCs, RNA and DNA was extracted from whole tumour (>85%), following similar strategies as previously described. This submission describes the copy number aberrations of 27 cervical SCC tissues and 10 common cervical SCC cell lines

ORGANISM(S): Homo sapiens

SUBMITTER: Ian Roberts

PROVIDER: E-GEOD-27673 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gain and overexpression of the oncostatin M receptor occur frequently in cervical squamous cell carcinoma and are associated with adverse clinical outcome.

Ng G G Winder D D Muralidhar B B Gooding E E Roberts I I Pett M M Mukherjee G G Huang J J Coleman N N

The Journal of pathology 20070701 3

For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2-14.3 (59%), 5p13.3 (65%), and 5p13.2-13.1 ...[more]

PMID: 17516585

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Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target 36 primary cervical SCC samples, and 10 cervical SCC cell lines were subject to 1 Mb aCGH using a dye swapped approach. Two samples were subject to repeat. (J Pathol. 2007 Jul;212(3):325-34.)

Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target aCGH of high grade late stage primary cervical SCCs obtained from the archives of the Kidwai Memorial Institute of Oncology,

Dataset Information

An integrated genomics approach for novel biomarker discovery in squamous cell cervical carcinoma

Publications

Gain and overexpression of the oncostatin M receptor occur frequently in cervical squamous cell carcinoma and are associated with adverse clinical outcome.

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