Dataset Information


MRE11 Deficiency Increases Sensitivity to Poly(ADP-ribose) Polymerase Inhibition in Microsatellite Unstable Colorectal Cancers.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Bhramar Mukherjee   Gad Rennert  Maria D Iniesta  Eduardo Vilar  Stephanie L Stenzel  Jaeil Ahn  Victor Moreno  Stephen B Gruber  Leon Raskin  Meredith A Morgan  Catherine M Bartnik 

PROVIDER: E-GEOD-26682 | ArrayExpress | 2011-04-07



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MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers.

Vilar Eduardo E   Bartnik Catherine M CM   Stenzel Stephanie L SL   Raskin Leon L   Ahn Jaeil J   Moreno Victor V   Mukherjee Bhramar B   Iniesta Maria D MD   Morgan Meredith A MA   Rennert Gad G   Gruber Stephen B SB  

Cancer research 20110207 7

Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells t  ...[more]

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