Abstract
BackgroundThe identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma.MethodsTranscriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.ResultsNine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway. Two recurrent fusion genes associated with the 12q locus, LRP1-SNRNP25 and KCNMB4-CCND3, were identified and validated by RT-PCR, Sanger sequencing and fluorescence in situ hybridization, and were found to be osteosarcoma specific in a validation cohort of 240 other sarcomas. Expression of LRP1-SNRNP25 fusion gene promoted SAOS-2 osteosarcoma cell migration and invasion. Expression of KCNMB4-CCND3 fusion gene promoted SAOS-2 cell migration.ConclusionsOur study represents the first whole transcriptome analysis of untreated human osteosarcoma. Our discovery of two osteosarcoma specific fusion genes associated with osteosarcoma cellular motility highlights the heterogeneity of osteosarcoma and provides opportunities for new treatment modalities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0076-2) contains supplementary material, which is available to authorized users.
Highlights
The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas
Two recurrent fusion genes associated with the 12q locus, LRP1SNRNP25 and KCNMB4-cyclin D3 (CCND3), were validated and investigated
Transcriptome sequencing cohort Sarcoma tissue and information collection for this study at Tianjin Medical University Cancer Institute & Hospital (TMUCIH) was performed according to the protocol approved by the Institutional Review Board (IRB) of TMUCHIH and with patient consent
Summary
The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma. Sarcomas were the first cancer type associated with chromosomal translocations and gene fusions [1]. ALK, BCOR-CCNB3 and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas [6,7,8,9,10]. Our discovery of novel osteosarcoma fusion genes and rearrangement hotspots provides important insight into the role that chromosomal rearrangements play in p53 pathway inactivation and regulation of cell motility in osteosarcoma cells
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