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Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of
Lu Wang1, Toru Motoi, Raya Khanin
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA.
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.
Insights
A novel bioinformatic screen identified the HEY1-NCOA2 gene fusion as a diagnostic marker for mesenchymal chondrosarcoma. This discovery aids in understanding cancer gene fusions and developing targeted therapies.
Area of Science:
- Genomics
- Bioinformatics
- Oncology
Background:
- Cancer gene fusions often result in chimeric proteins and altered RNA expression levels.
- Detecting these fusions is crucial for cancer diagnosis and understanding oncogenesis.
Purpose of the Study:
- To develop a genome-wide bioinformatic screen for identifying cancer gene fusions.
- To discover novel gene fusions and their diagnostic potential in sarcomas.
Main Methods:
- Development of the Fusion Score (FS) model using Affymetrix Exon array data.
- Genome-wide screening of tumor samples for intragenic expression changes indicative of fusions.
- Validation of candidate fusions using 5' RACE, RT-PCR, and FISH.
Main Results:
- The FS model identified 552 candidate genes in 41 tumor samples.
- A novel HEY1-NCOA2 fusion was identified in mesenchymal chondrosarcoma and confirmed in 9 additional cases.
- This HEY1-NCOA2 fusion was absent in other chondrosarcoma subtypes, suggesting diagnostic specificity.
- A NUP107-LGR5 fusion was found in dedifferentiated liposarcoma but was not recurrent.
Conclusions:
- The HEY1-NCOA2 fusion is a defining and diagnostic marker for mesenchymal chondrosarcoma.
- The developed bioinformatic approach is effective for unbiased, genome-wide gene fusion discovery.
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