Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genomic alterations and gene expression in primary diffuse large B cell lymphomas of immune privileged sites

ABSTRACT: Primary diffuse large B cell lymphomas of different immune-privileged sites (IP-DLBCL) share many clinical and biological features, such as a relatively poor prognosis, preferential dissemination to other immune-privileged sites and deletion of the HLA region, which suggests that IP-DLBCL represents a separate entity. To further investigate the nature of IP-DLBCL, we investigated site-specific genomic aberrations in 16 testicular, 9 central nervous system (CNS) and 15 nodal DLBCL using array-CGH. We also determined minimal common regions of gain and loss. Using robust algorithms, the array-CGH data were combined with gene expression data to explore pathways deregulated by chromosomal aberrations. Keywords: comparative genomic hybridisation, gene expression, tumor type comparison Whole tissue sections of 16 testicular, 9 central nervous system (CNS) and 15 nodal DLBCL were used for isolation of genomic DNA and total RNA. Genomic aberrations were determined using an in house printed CGH array containing ~3700 large genomic insert clones. Gene expression was analyzed on Affymetrix HU133 plus 2.0 oligo arrays. Gene expression data and arrayCGH data were combined using the R program ACE-it.

ORGANISM(S): Homo sapiens

SUBMITTER: Marije Booman

PROVIDER: E-GEOD-10524 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways.

Booman M M Szuhai K K Rosenwald A A Hartmann E E Kluin-Nelemans Hc H de Jong D D Schuuring E E Kluin Pm P

The Journal of pathology 20081001 2

Primary diffuse large B-cell lymphomas of different immune-privileged sites (IP-DLBCLs) share many clinical and biological features, such as a relatively poor prognosis, preferential dissemination to other immune-privileged sites, and deletion of the HLA region, which suggests that IP-DLBCL represents a separate entity. To further investigate the nature of IP-DLBCL, we investigated site-specific genomic aberrations in 16 testicular, nine central nervous system (CNS), and 15 nodal DLBCLs using ar ...[more]

PMID: 18729069

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Project description:We superimposed array comparative genomic hybridization (aCGH) data onto existing expression array profiles (GSE3892) to sift out the pivotal genes underlying the pathogenesis of a well defined series of diffuse large B-cell lymphomas (DLBCL). 280 gained and over-expressed genes were identified, located on chromosomes 1q, 3q, 7, 12p12, 18q and 21q. At the most frequently gained region the oncogene MDMX/MDM4 was concurrently over-expressed, which is a critical regulator of p53 function. In regions of frequent chromosomal loss, 36 genes were concurrently down-regulated, restricted to 6q and 15p. These putative tumor suppressor genes included PERP, MAP3K5, CCNDBP1 and Î²2M, and loss of 6q was associated with poor clinical outcome. Genes identified and chromosomal regions validated in an independent series of DLBCL patients. Overall design fields: Copy number profiles (array CGH) of a series of 42 Diffuse large B-cell lymphoma patient samples were analyzed a) for frequency of aberrations and b) for impact on gene expression. No duplicate samples or dye-swaps were analyzed. a) Statistical analysis of Array CGH data Calling: Areas of gains and losses and their frequencies throughout the dataset were determined from the Bluefuse ratios within the statistical package â??CGHcallâ?? (van de Wiel et al., 2007). Briefly, after smoothing outliers and median normalization, â??DNAcopyâ?? segmentation (Olshen et al., 2004) was applied within CGHcall, after which a call was assigned to each position on the genome. Within CGHcall the probabilities of the calls were determined per chromosomal arm, and a cellularity correction of 0.75 was applied to each sample because tumor cellularity in all DLBCL is estimated to be maximal 75%, taking into account all stromal, endothelial en infiltrating lymphocytes. After calling, we applied â??CGHregionsâ?? (van de Wiel and van Wieringen 2007) to determine regions of consecutive clones with highly similar calls for all samples. This dimension reduction further increases robustness and statistical power for downstream statistical analyses. Called data were used for all downstream analyses. b) Integration with expression data To integrate called array CGH data with expression array data, the array CGH and expression integration tool, ACE-it (van Wieringen et al., 2006), was used. For ACE-it analysis chromosomal amplifications were included in the gains. ACE-it uses the one-sided Wilcoxon rank sum to test which chromosomal aberrations recurrently affect RNA expression and adjust p-values for multiple testing. Only those clones were taken into account which had at least 20% (9) of the samples in one of the other calling states (gain or loss). Only genes were considered relevant with a false discovery rate of <0.1. References - Olshen AB, Venkatraman ES, Lucito R, Wigler M (2004) Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5: 557-72. - van de Wiel MA, Kim KI, Vosse SJ, van Wieringen WN, Wilting SM, Ylstra B (2007) CGHcall: calling aberrations for array CGH tumor profiles. Bioinformatics 23: 892-4. - van de Wiel MA, van Wieringen WN. CGHregions: dimension reduction for array CGH data with minimal information loss. Cancer Informatics. In press 2007. - van Wieringen WN, Belien JA, Vosse SJ, Achame EM, Ylstra B (2006) ACE-it: a tool for genome-wide integration of gene dosage and RNA expression data. Bioinformatics 22: 1919-20.

Project description:Introduction: In breast cancers, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations as well, as shown by a previously described micro-event in the PTEN gene in the Basal-like SUM149 breast cancer cell line. Methods: We sought to identify if small regions of genomic change exist by using a high density, gene centric Comparative Genomic Hybridizations (CGH) array on both cell lines and primary tumors. A custom Agilent tiling array for CGH (244,000 probes, 200bp tiling resolution) was created to identify small regions of genomic change and was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments being called micro-aberrations (<64 contiguous probes, ~ <15kb). Results: Our data showed that primary tumor breast cancer genomes frequently contained areas of small-scale copy number gains and losses, termed micro-aberrations, which are undetectable using lower-density genome-wide platforms. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene as suggested by data from microarray and mRNA-seq studies. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5’ regions of the affected genes, including the promoter region, and a high frequency of micro-aberrations was associated with poor survival outcomes. Conclusion: Using a high probe density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that contribute to gene inactivation, and thus, genomic instability and tumor formation through a mechanism not detected using conventional copy number analyses. reference x sample

Dataset Information

Genomic alterations and gene expression in primary diffuse large B cell lymphomas of immune privileged sites

Publications

Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways.

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