Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets.

Project description:IntroductionThe bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.Materials and methodsWe utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.ResultsMolecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.DiscussionOverall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.

Dataset Information

Nuclear division cycle 80 complex is associated with malignancy and predicts poor survival of hepatocellular carcinoma.

Publications

Nuclear division cycle 80 complex is associated with malignancy and predicts poor survival of hepatocellular carcinoma.

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