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Adrenocortical Carcinoma Gene Expression Profiling [Agilent]

ABSTRACT: Adrenocortical carcinoma (ACC) is an aggressive endocrine tumor with a poor 5 year survival rate of 10-20%. We used expression profiling to assess the transcriptional changes associated with ACC as compared to normal adrenal glands with the goal of identifying new targets for treatment. Fourteen ACC tumors were profiled on both Affymetrix U133 Plus 2 or Agilent 22K Human Genome arrays; an additional six tumors were profiled on one or the other array. The data demonstrate a marked dysregulation of the cell cycle control, focused on sister chromatid adhesion and cytokinesis in the G2/M transistion. Genes associated with this pattern, and identified because of coordinate expression with CDC2, were capable of clustering ACC into two clusters that almost completely recapitulated histological grade. Exploration of the data sets by both Gene Set Enrichment Analysis and GeneGo Interactome analysis identified additional dysregulation of the IGF2-IGF1R axis, aside from IGF2 over-expression, as an early event present in low grade tumors. Additionally, p53 and MDM2 were consistently identified as drivers in leading edge analyses of the tumors, implicating the p53 pathway in ACC pathogenesis. Finally, over-expression of PTTG1, which encodes securin, and is involved in sister chromatid adhesion as well as negative regulation of p53, was associated with poor prognosis in our samples. Taken together, these data point toward a tumor type driven in part by dysregulated IGF2 signaling in the context of a lack of a functional p53 response, with potential vulnerabilities in the G2/M transition that may make viable therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19775 | GEO | 2013/11/21

SECONDARY ACCESSION(S): PRJNA124015

REPOSITORIES: GEO

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Project description:Adrenocortical carcinoma (ACC) is an aggressive endocrine tumor with a poor 5 year survival rate of 10-20%. We used expression profiling to assess the transcriptional changes associated with ACC as compared to normal adrenal glands with the goal of identifying new targets for treatment. Fourteen ACC tumors were profiled on both Affymetrix U133 Plus 2 or Agilent 22K Human Genome arrays; an additional six tumors were profiled on one or the other array. The data demonstrate a marked dysregulation of the cell cycle control, focused on sister chromatid adhesion and cytokinesis in the G2/M transistion. Genes associated with this pattern, and identified because of coordinate expression with CDC2, were capable of clustering ACC into two clusters that almost completely recapitulated histological grade. Exploration of the data sets by both Gene Set Enrichment Analysis and GeneGo Interactome analysis identified additional dysregulation of the IGF2-IGF1R axis, aside from IGF2 over-expression, as an early event present in low grade tumors. Additionally, p53 and MDM2 were consistently identified as drivers in leading edge analyses of the tumors, implicating the p53 pathway in ACC pathogenesis. Finally, over-expression of PTTG1, which encodes securin, and is involved in sister chromatid adhesion as well as negative regulation of p53, was associated with poor prognosis in our samples. Taken together, these data point toward a tumor type driven in part by dysregulated IGF2 signaling in the context of a lack of a functional p53 response, with potential vulnerabilities in the G2/M transition that may make viable therapeutic targets. RNA from fifteen adrenocortical carcinomas and a pool of four normal adrenal glands was extracted, labeled, and hybridized to Agilent Human 1A Oligo Microarray (v2) chips. The resulting data was first background subtracted. Each array then had the median intenisty subtracted from each channel, and finally both M and A values were quantile normalized across arrays. All calculations were done in R using the Bioconductor packages of marray and limma.

Project description:Background: Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data prognostic biomarkers and novel therapeutic targets. Methods: 44 ACC and 4 normal adrenal glands were profiled on Affymetrix U133 Plus 2 expression microarrays and pathway and transcriptional enrichment analysis performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed as validation data sets. Results: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). These findings were confirmed by our analysis of previously published datasets. Treatment of ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively). Conclusion: Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target. RNA from forty-four adrenocortical carcinomas and four normal adrenal glands was extracted, labeled, and hybridized to Affymetrix U133 Plus 2 arrays. The resulting data was normalized by gcRMA with quantile normalization and background subtraction after using the ExpressionFileCreator in GenePattern. Data was then floored at 5.5 using PreprocessDataset, and filtered to remove 1) probes with more than 35 floored values and/or 2) probes where all values from one batch were floored while values from the other batch were not. Further batch effects were minimized using ComBat with the parametric option. Data was then floored at 2. Differentially expressed genes were determined using a T-test with multiple comparison correction as implemented by Comparative Marker Selection in Gene Pattern. Genes with the corrected p-value < 0.005 and the FDR < 0.075 were selected for further study. For comparing high to low grade or primary to recurrence, the FDR cut-off was increased to < 0.13. Survival analysis was conducted using Prism 6 (GraphPad) to generate Kaplan-Meier curves that were compared by log-rank.

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Adrenocortical Carcinoma Gene Expression Profiling [Agilent]

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