Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of eight candidate target genes of the prognsotic 3p loss in cervical cancer by integrative genomic profiling

ABSTRACT: We performed integrative gene dosage and expression profiling to identify candidate target genes of the prognostic 3p loss in cervical cancer. Candidate target genes were proposed from the correlation between gene dosage and gene expression. Combined network, gene set, and gene ontology analysis of the gene expression profiles depicted interaction partners of the candidate targets and proposed biological processes that were affected by the 3p loss. Gene dosages from array CGH data (previously submiited to ArrayExpress) were correlated with Illumina gene expression data in the integrative patient cohort. The prognostic significance of the candidate target genes was validated based on the Illumina gene expression data of the validation cohort. Changes in gene expressions after knockdown of three candidate targets, RYBP, TMF1 and PSMD6, were studied by Illumina beadarrays in the cervical cancer cell lines HeLa, SiHa and CaSki.

ORGANISM(S): Homo sapiens

SUBMITTER: Heidi Lyng

PROVIDER: E-GEOD-38964 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.

Lando Malin M Wilting Saskia M SM Snipstad Kristin K Clancy Trevor T Bierkens Mariska M Aarnes Eva-Katrine EK Holden Marit M Stokke Trond T Sundfør Kolbein K Holm Ruth R Kristensen Gunnar B GB Steenbergen Renske D M RD Lyng Heidi H

The Journal of pathology 20130314 1

The pathogenetic role, including its target genes, of the recurrent 3p12-p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high-grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during ...[more]

PMID: 23335387

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Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates

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Dataset Information

Identification of eight candidate target genes of the prognsotic 3p loss in cervical cancer by integrative genomic profiling

Publications

Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.

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