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Purpose: We report a novel analytic method, named intercohort co-analysis or Ican, which aids in the discovery of genes with predictive value for the progression or outcome of diseases from small-size cohorts. We tested this premise in Ewing's sarcoma (ES), a highly metastatic cancer of bone and soft tissues that lacks validated molecular metastasis and prognostic indicators.Experimental Design: To uncover genes significantly expressed in ES patient subsets, we first determined a nonarbitrary gene expression significance cutoff based on expression levels in validated expressing and nonexpressing tissues. We next searched for genes that were consistently significantly expressed in several ES cohort and cell line datasets. Significantly expressed genes were independently validated by quantitative reverse transcription-PCR in an additional ES cohort.Results: Analysis of ES cohorts revealed marked intercohort gene expression variability. After filtering out the intercohort variability, CXCR4 and CXCR7 were found to be consistently associated with specific ES subsets. Pairwise analyses showed CXCR4 to correlate with ES metastases, and CXCR4 and CXCR7 to patient survival, but not with several other clinicopathological variables.Conclusion: Ican is a powerful novel method to identifying genes consistently associated with particular disease states in cancers for which large cohorts are not available, currently the case of most cancers. We report for the first time that high CXCR4 expression preferentially associates with metastatic ES, and that of CXCR7 with poor patient survival. Clin Cancer Res; 16(14); 3769–78. ©2010 AACR.

Supplementary Data from Intercohort Gene Expression Co-Analysis Reveals Chemokine Receptors as Prognostic Indicators in Ewing's Sarcoma

Supplementary Figure Legend 1, Table Legends 1-6 from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

Supplementary Figure 1 from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

Supplementary Table 7 from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

Supplementary Table 9 from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

Hypoxia is an important condition in the tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. Because, by immunohistochemistry, HIF-1α expression was readily detectable in 18 of 28 primary Ewing's sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, we studied the effect of hypoxia on ESFT cell lines in vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by hypoxia in a HIF-1α–dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis-related genes, hypoxia stimulated the invasiveness and soft agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Cancer Res; 70(10); 4015–23. ©2010 AACR.

Supplementary Tables 1-6 from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

Supplementary Table 8b from Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro

The Human Immunodeficiency Virus (HIV) has a diversity that is equal to the complexity of its management. The group M (Major) is the dominant group in Sub-Saharan Africa and its distribution is very heterogeneous; the diversity of the virus is more heterogeneous in this region than elsewhere in the world which follows a complex and specific algorithm because of geographical positions and countries. This distribution is very dynamic, evolving and unpredictable. This review aimed to expose the specifics of the HIV Type 1 epidemic in Central Africa, in terms of the different molecular variants of HIV published for the region compared to the geographic location. Both Type 1 and Type 2 of HIV are prevalent in sub-Saharan Africa due to distinct geographical contexts. HIV-2 is mainly documented in West and Central Africa, particularly in Cameroon, Guinea-Bissau, Gambia, Senegal, Ivory Coast and Burkina-Faso however HIV-1 infection is widely distributed across the continent. The HIV-1 epidemic in Sub-Saharan Africa is dominated by the Group M. The different subtypes respect a certain geographical distribution across the continent. West Africa is dominated by subtype A, East and South Africa are dominated by subtype C, while Central Africa is dominated by strains A, C, D, F, H, J, CRF01-AE and CRF02-AG. This review is the first to present de molecular diversity of HIV-1 in metropolitan cities in all central African countries. The Circulating Recombinant Form (CRF02_AG) and subtypes A and G are present in all Central African countries and are also the most commonly encountered; followed by the subtypes D, F, G, C, B, J, K and several Circulating Recombinant Forms that are not represented in all Central African countries.