Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Microsatellite stable (n=38) and instable-high (n=13) human colorectal tumors assayed with Affymetrix HuGeneFL arrays.

ABSTRACT: mRNA assays were performed on 51 samples of human colorectal tumors using Affymetrix HuGeneFL arrays containing 7129 probe-sets. We compared 38 microsatelite stable (MSS) tumors with 13 microsatellite instable-high (MSI) tumors to form a list of genes differing between the two types. In order to identify molecular signatures characterizing MSI tumors, we examined only MSI-high cancers and not MSI-low ones. Keywords: disease state analysis Human samples of 38 microsatellie stable and 13 microsatellite instable-high colorectal tumors, each from a separate patient, had mRNA assays performed using Affymetrix HuGeneFL arrays, with 7129 probe-sets. A supplementary Excel file (Colon_HuFL_logs.xls) is attached below that gives the log-transformed probe-set values. It also gives the p-values from T-tests comparing these values between MSS and MSI samples, as well as an estimated average fold-difference, for which the mathematical functions are explicitly given.

ORGANISM(S): Homo sapiens

SUBMITTER: Rork Kuick

PROVIDER: E-GEOD-11543 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway.

Vilar Eduardo E Mukherjee Bhramar B Kuick Rork R Raskin Leon L Misek David E DE Taylor Jeremy M G JM Giordano Thomas J TJ Hanash Samir M SM Fearon Eric R ER Rennert Gad G Gruber Stephen B SB

Clinical cancer research : an official journal of the American Association for Cancer Research 20090407 8

<h4>Purpose</h4>High-frequency microsatellite-instable (MSI-H) tumors account for approximately 15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets.<h4>Experimental design</h4 ...[more]

PMID: 19351759

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Project description:We have performed bioinformatic approaches to identify the level of enrichment between gene expression profiles characterizing MSI tumors and gene changes induced in vitro by the PARP-1 inhibitor Phenanthridinone and others using the Connectivity Map tool. In a first step, we have anyzed the expression of 300 colorectal cancers from the MECC study and generated a gene expression signature by microsatellite status. The criteria followed for selection of probe sets and detailed lists to be submitted subsequently to the Connectivity Map have been published previously by us in Clinical Cancer Research in 2009. In a second step, once we observed that deficiency in MRE11 exist among MSI tumors, our interest was focused on assessing if the homologous recombination pathway showed evidence of deregulation in MSI tumors. Therefore, we examined the expression levels of those genes integrated in the KEGG pathway hsa03440 using the previously generated gene expression data set. The dataset generated from our samples included a total of 300 colorectal fresh frozen tumors collected from the MECC study and were analyzed in two batches. The first batch was hybridized to the Affymetrix U133A chip and the second one to U133 Plus 2.0 (Supplementary Table S3). The final list of probe sets defining gene expression of MSI-H compared to MSS tumors was selected based on the strength of multiplicity adjusted P-values (cut-off P-value of < 0.001) and ratio of mean expression values across the two groups (cut-off Fold-change >1.3 and <0.7). It contained 442 upregulated and 480 downregulated probe sets. Then, MSI-H tumors present with changes in gene expression related to the homologous recombination pathway. Therefore, we examined the expression levels of those genes integrated in the KEGG pathway hsa03440 using the same data set. A total of 14 genes out of 30 were significantly differentially expressed in MSI-H compared to MSS tumors (Multiplicity adjusted Benjamini-Hochberg P-value<0.05). MRE11 and RAD50 probe sets showed a lower expression in MSI-H tumors and simultaneously other probe sets such as PARP-1 were significantly upregulated, probably secondary to the deficiency in the MRN complex proteins. This data provides evidence of significant differential expression of the homologous recombination pathway in MSI tumors.

Project description:We compared the expression of genes related to inflammatory cytotoxic functions between MSI and MSS (HLA class I negative and positive) gastrointestinal adenocarcinomas (GIACs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two GIACs were divided into three study groups as a function of HLA class I expression and MSI phenotype. Comparison between eight high-level MSI (MSI-H) and 8 MSS/HLA+ (control) cancers identified 2170 differentially expressed genes (p< 0.05) after microarray analysis on the Affymetrix HG-U133-Plus-PM plate. We grouped genes in Gene Ontology functional categories: apoptotic programme (119 genes, p=5.1·10-7), leukocyte activation (32 genes, p=0.01), T cell activation (20 genes, p= 0.01), and cytokine production (19 genes, p= 0.04). Real-time RT-PCR and immunohistochemical evaluation were used to confirm some microarray data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+ T lymphocytes in the MSI-H group (p<0.001). Finally, tumours with immunohistochemical HLA class I negative pattern were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-ABC negative CRCs. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumours, MSI/HLA- and MSS/HLA-, showed marked differences in the composition and intensity of infiltrating leukocytes, suggesting that their immune escape strategies involve distinct pathways. Case-control study. Samples were selected according to immunological criteria: those with total loss of HLA antigens and those without alterations in the expression of HLA molecules. In addition, the microsatellite instability genotype of all the samples was also analyzed, resulting in microsatellite stability (MSS) and microsatellite instability (MSI) samples. Therefore, three groups of samples were selected: MSS/HLA+, MSS/HLA-, and MSI. The MSS/HLA+ group was used as the control.

Dataset Information

Microsatellite stable (n=38) and instable-high (n=13) human colorectal tumors assayed with Affymetrix HuGeneFL arrays.

Publications

Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway.

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