Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 Fusion Genes Promote Tumor Cell Motility in Human Osteosarcoma

J Hematol Oncol. 2014 Oct 10;7:76. doi: 10.1186/s13045-014-0076-2.

Abstract

Background: 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.

Methods: Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas.

Results: Nine 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.

Conclusions: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Movement / genetics*
  • Cohort Studies
  • Cyclin D3 / genetics*
  • Female
  • Gene Fusion*
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits / genetics*
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Osteosarcoma / genetics*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Ribonucleoproteins, Small Nuclear / genetics*
  • Transcriptome
  • Young Adult

Substances

  • CCND3 protein, human
  • Cyclin D3
  • KCNMB4 protein, human
  • LRP1 protein, human
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Nerve Tissue Proteins
  • Ribonucleoproteins, Small Nuclear
  • SNRNP25 protein, human