Identification of a Novel, Recurrent HEY1-NCOA2 Fusion in Mesenchymal Chondrosarcoma Based on a Genome-Wide Screen of Exon-Level Expression Data.
Lu Wang, Toru Motoi, Raya Khanin, Nicholas Socci, Adam Olshen, Fredrik Mertens, Julia Bridge, Paola Dal Cin, Elisabeth J Rushing, Julie Fanburg-Smith, Cristina Antonescu, Meera Hameed, Marc Ladanyi. Memorial Sloan-Kettering Cancer Center, New York, NY; Lund University Hospital, Lund, Sweden; University of Nebraska Medical Center, Omaha; Brigham & Women's Hospital, Boston, MA; AFIP, Washington, DC; Inova Fairfax Hospital, Falls Church, VA
Background: Cancer gene fusions that lead to the formation of a chimeric protein are often characterized by an intragenic discontinuity in the expression levels of the exons that are 5' or 3' to the fusion point in one or both of the fusion partners. Based on this, we developed an unbiased, genome-wide bioinformatic screen for this feature of gene fusions using Affymetrix Exon array expression data and report here its successful application in the identification of a new, recurrent sarcoma gene fusion.
Design: We studied 87 samples from 13 tumor cell lines and 74 tumor tissues, including 46 samples with different known gene fusions confirmed by RT-PCR. RNAs were hybridized to Affymetrix Exon 1.0 chips, providing coverage of essentially all protein-coding genes. A custom data analysis pipeline, the “Fusion Score (FS) model”, was developed to score genes for intragenic changes in expression. The FS was computed for each gene in each sample. Genes with high FS in normal control samples were excluded, while the remaining genes with “true” high FS were considered as candidates for further investigation.
Results: The FS model data analysis pipeline was trained using the data from the 46 cases with known fusions. In the remaining 41 tumor samples of various histologies (including 28 mesenchymal or embryonal tumors) with possible unknown gene fusions, the FS model generated a list of 606 candidate genes showing, in one or more samples of a given histology, significant intragenic changes in expression not seen in control samples. The transcription factor gene NCOA2 was one of the candidates identified in a mesenchymal chondrosarcoma. 5' RACE was performed, and a novel HEY1-NCOA2 fusion was isolated, representing an in-frame fusion of HEY1 exon 3 to NCOA2 exon 13, encoding a predicted protein including the HEY1 DNA binding domain and the NCOA2 activation domain. Another 8 mesenchymal chondrosarcoma cases were screened, and the same HEY1-NCOA2 fusion was identified in 2 more cases.
Conclusions: The present approach is able to identify fusion transcripts without any prior knowledge of the genetics of a given case or tumor type. The novel HEY1-NCOA2 fusion is the first recurrent gene fusion identified in mesenchymal chondrosarcomas.
Category: Bone & Soft Tissue
Monday, February 28, 2011 11:00 AM
Platform Session: Section F, Monday Morning