Dataset Information

Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes.

ABSTRACT: DNA copy number aberrations (CNAs) and gene expression (GE) changes provide valuable information for studying chromosomal instability and its consequences in cancer. While it is clear that the structural aberrations and the transcript levels are intertwined, their relationship is more complex and subtle than initially suspected. Most studies so far have focused on how a CNA affects the expression levels of those genes contained within that CNA.To better understand the impact of CNAs on expression, we investigated the correlation of each CNA to all other genes in the genome. The correlations are computed over multiple patients that have both expression and copy number measurements in brain, bladder and breast cancer data sets. We find that a CNA has a direct impact on the gene amplified or deleted, but it also has a broad, indirect impact elsewhere. To identify a set of CNAs that is coordinately associated with the expression changes of a set of genes, we used a biclustering algorithm on the correlation matrix. For each of the three cancer types examined, the aberrations in several loci are associated with cancer-type specific biological pathways that have been described in the literature: CNAs of chromosome (chr) 7p13 were significantly correlated with epidermal growth factor receptor signaling pathway in glioblastoma multiforme, chr 13q with NF-kappaB cascades in bladder cancer, and chr 11p with Reck pathway in breast cancer. In all three data sets, gene sets related to cell cycle/division such as M phase, DNA replication and cell division were also associated with CNAs. Our results suggest that CNAs are both directly and indirectly correlated with changes in expression and that it is beneficial to examine the indirect effects of CNAs.The code is available upon request.

SUBMITTER: Lee H

PROVIDER: S-EPMC2600603 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes.

Lee Hyunju H Kong Sek Won SW Park Peter J PJ

Bioinformatics (Oxford, England) 20080208 7

<h4>Motivation</h4>DNA copy number aberrations (CNAs) and gene expression (GE) changes provide valuable information for studying chromosomal instability and its consequences in cancer. While it is clear that the structural aberrations and the transcript levels are intertwined, their relationship is more complex and subtle than initially suspected. Most studies so far have focused on how a CNA affects the expression levels of those genes contained within that CNA.<h4>Results</h4>To better underst ...[more]

PMID: 18263644

Similar Datasets

Project description:Background: Lung cancer has the highest mortality rate of all the cancers in the world and asbestos-related lung cancer is one of the leading occupational cancers. The identification of the asbestos-related molecular changes has been a topic of major research interest over the years. The aim of the current study was to identify novel asbestos-related molecular correlates by integrating miRNA expression profiling with previously obtained microarray data (aCGH and mRNA expression) from the same patient material. Results: Twelve novel asbestos-related miRNAs (over-expressed: miR-148b, miR-374a, miR-24-1*, Let-7d, Let-7e, miR-199b-5p, miR-331-3p and under-expressed: miR-939, miR-671-5p, miR-605, miR-1224-5p, miR-202) which inversely correlated with target genes (e.g. GADD45A, LTBP1, FOSB, NCALD, CACNA2D2, MTSS1, EPB41L3) were identified. In addition, several known and new lung cancer-associated miRNAs were identified. DNA copy number alterations were also correlated with the deregulation of four miRNAs in lung cancer. The importance of integrated analysis was highlighted by the interesting finding of linking of the over-expression of well known squamous cell carcinoma-associated miR-205 with the down-regulation of the gene DOK4. Conclusions: Novel deregulated miRNAs and inversely correlating expression of target genes associated with lung cancer etiology and histology were identified. In addition, DNA copy number alterations correlated with the deregulation of some of the miRNAs. The results of the current study could have potential diagnostic implications, but require further investigation. Methods: The patient material used in the study consisted of 26 tumour and normal lung tissue from highly asbestos-exposed (13 samples) and non-exposed (13 samples) patients. Control lung tissue samples were obtained from 7 patients without cancer as well as from a commercial lung tissue RNA. Data analysis on miRNA expression and integration of miRNA and mRNA data were performed using Chipster (http://chipster.csc.fi/). In addition, miRNA and aCGH data were integrated in a separate analysis. *** This submission represents the microRNA component of the study

Project description:Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range?=?0.60-21.78) and 8.60 years (range?=?3.08-13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ?1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01×10(-5)) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10(-5)) when analyses were restricted to stratified cases (luminal A, n?=?208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.

Dataset Information

Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes.

Publications

Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets