Dataset Information

Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data.

ABSTRACT: Cancer gene fusions that encode a chimeric protein are often characterized by an intragenic discontinuity in the RNA\expression levels of the exons that are 5' or 3' to the fusion point in one or both of the fusion partners due to differences in the levels of activation of their respective promoters. Based on this, we developed an unbiased, genome-wide bioinformatic screen for gene fusions using Affymetrix Exon array expression data. Using a training set of 46 samples with different known gene fusions, we developed a data analysis pipeline, the "Fusion Score (FS) model", to score and rank genes for intragenic changes in expression. In a separate discovery set of 41 tumor samples with possible unknown gene fusions, the FS model generated a list of 552 candidate genes. The transcription factor gene NCOA2 was one of the candidates identified in a mesenchymal chondrosarcoma. A novel HEY1-NCOA2 fusion was identified by 5' RACE, representing an in-frame fusion of HEY1 exon 4 to NCOA2 exon 13. RT-PCR or FISH evidence of this HEY1-NCOA2 fusion was present in all additional mesenchymal chondrosarcomas tested with a definitive histologic diagnosis and adequate material for analysis (n = 9) but was absent in 15 samples of other subtypes of chondrosarcomas. We also identified a NUP107-LGR5 fusion in a dedifferentiated liposarcoma but analysis of 17 additional samples did not confirm it as a recurrent event in this sarcoma type. The novel HEY1-NCOA2 fusion appears to be the defining and diagnostic gene fusion in mesenchymal chondrosarcomas.

SUBMITTER: Wang L

PROVIDER: S-EPMC3235801 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Publications

Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data.

Wang Lu L Motoi Toru T Khanin Raya R Olshen Adam A Mertens Fredrik F Bridge Julia J Dal Cin Paola P Antonescu Cristina R CR Singer Samuel S Hameed Meera M Bovee Judith V M G JV Hogendoorn Pancras C W PC Socci Nicholas N Ladanyi Marc M

Genes, chromosomes & cancer 20111027 2

Cancer gene fusions that encode a chimeric protein are often characterized by an intragenic discontinuity in the RNA\expression levels of the exons that are 5' or 3' to the fusion point in one or both of the fusion partners due to differences in the levels of activation of their respective promoters. Based on this, we developed an unbiased, genome-wide bioinformatic screen for gene fusions using Affymetrix Exon array expression data. Using a training set of 46 samples with different known gene f ...[more]

PMID: 22034177

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Project description:Mesenchymal chondrosarcoma is a rare and often aggressive cancer that accounts for 2-10% of all chondrosarcomas. Genetically, this tumor is characterized by the recurrent HEY1-NCOA2 fusion. However, the oncogenic function of HEY1-NCOA2 fusion in mesenchymal chondrosarcoma remains to be elucidated. We stably transduced HEK293 as well as iPSC-derived mesenchymal stem cells (MSCs) with inducible- expression HEY1, NCOA2 and HEY1-NCOA2 construct, respectively. Using the stably transduced cell lines, we investigated the intracellular localization of HEY1-NCOA2 fusion protein and performed genome-wide chromatin Immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq) to identify HEY1-NCOA2-dependent transcriptional regulation. In this study, HEY1-NCOA2 fusion protein was found to be localized to the nucleus, like wild-type HEY1; and extreme similarity in genome-wide DNA-binding pattern between HEY1-NCOA2 and wild-type HEY1 was observed. By gene expression profiling, HEY1-NCOA2-expression (MSC-HN+), HEY1-expression (MSC-HEY1+) and NCOA2-expression (MSC-NCOA2+) iPSC-MSCs can be robustly separated, and the combined differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA) revealed that genes downregulated by HEY1 were positively enriched in MSC-HN+ versus control. Functional classification of HEY1-NCOA2 upregulated genes according to KEGG networks highlighted various pathways related to promoting cell proliferation in cancer, such as cell cycle pathway, Hedgehog and WNT signaling as well as PI3K-Akt signaling pathways. Indeed, MSC-HN+ cells displayed significantly accelerated proliferation and a significant increase in cell cycle transit when compared with control cells. In 3D spheroidal growth model, we also observed both accelerated cell proliferation and distinct morphological features of the MSC-HN+ cells in contrast to the control cells. Our data provide functional evidence that HEY1-NCOA2 fusion protein preferentially binds to DNA regions that are originally occupied by the wild-type HEY1 transcription factor, and the expression of some HEY1 target genes as well as their related pathways, that are normally repressed by HEY1, are activated in the presence of HEY1-NCOA2 fusion protein.

Dataset Information

Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data.

Publications

Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data.

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