3 results on '"Integrative genomic profiling"'
Search Results
2. Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.
- Author
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Lando, Malin, Wilting, Saskia M, Snipstad, Kristin, Clancy, Trevor, Bierkens, Mariska, Aarnes, Eva‐Katrine, Holden, Marit, Stokke, Trond, Sundfør, Kolbein, Holm, Ruth, Kristensen, Gunnar B, Steenbergen, Renske DM, and Lyng, Heidi
- Abstract
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 the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down-regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down-regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight-gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12-p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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3. Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer
- Author
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Heidi Lyng, Saskia M. Wilting, Malin Lando, Renske D.M. Steenbergen, Eva Katrine Aarnes, Gunnar B. Kristensen, Christina S. Fjeldbo, Malin F. Forsberg, Barbara C. Snoek, Center of Experimental and Molecular Medicine, Pathology, and CCA - Oncogenesis
- Subjects
Adult ,Cancer Research ,Carcinogenesis ,Tumor suppressor genes ,Uterine Cervical Neoplasms ,Kaplan-Meier Estimate ,Biology ,medicine.disease_cause ,Gene dosage ,Disease-Free Survival ,Epigenesis, Genetic ,FHIT ,medicine ,Humans ,Gene silencing ,Gene Silencing ,Promoter Regions, Genetic ,Molecular Biology ,Aged ,3p ,Cancer ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Promoter methylation ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,CpG site ,DNA methylation ,Cancer research ,Cervical cancer ,CpG Islands ,Female ,Chromosomes, Human, Pair 3 ,Chromosomal loss ,Gene expression ,Chromosome Deletion ,Integrative genomic profiling ,Research Paper - Abstract
Loss of 3p11-p14 is a frequent event in epithelial cancer and a candidate prognostic biomarker in cervical cancer. In addition to loss, promoter methylation can participate in gene silencing and promote tumor aggressiveness. We have performed a complete mapping of promoter methylation at 3p11-p14 in two independent cohorts of cervical cancer patients (n = 149, n = 121), using Illumina 450K methylation arrays. The aim was to investigate whether hyperm-ethylation was frequent and could contribute to gene silencing and disease aggressiveness either alone or combined with loss. By comparing the methylation level of individual CpG sites with corresponding data of normal cervical tissue, 26 out of 41 genes were found to be hypermethylated in both cohorts. The frequency of patients with hypermethylation of these genes was found to be higher at tumor stages of 3 and 4 than in stage 1 tumors. Seventeen of the 26 genes were transcriptionally downregulated in cancer compared to normal tissue, whereof 6 genes showed a significant correlation between methylation and expression. Integrated analysis of methylation, gene dosage, and expression of the 26 hypermethylated genes identified 3 regulation patterns encompassing 8 hypermethylated genes; a methylation driven pattern (C3orf14, GPR27, ZNF717), a gene dosage driven pattern (THOC7, PSMD6), and a combined methylation and gene dosage driven pattern (FHIT, ADAMTS9, LRIG1). In survival analysis, patients with both hypermethylation and loss of LRIG1 had a worse outcome compared to those harboring only hypermethylation or none of the events. C3orf14 emerged as a novel methylation regulated suppressor gene, for which knockdown was found to promote invasive growth in human papilloma virus (HPV)-transformed keratinocytes. In conclusion, hypermethylation at 3p11-p14 is common in cervical cancer and may exert a selection pressure during carcinogenesis alone or combined with loss. Information on both events could lead to improved prognostic markers.
- Published
- 2015
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