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Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma.

Yang J, Annala M, Ji P, Wang G, Zheng H, Codgell D, Du X, Fang Z, Sun B, Nykter M, Chen K, Zhang W - J Hematol Oncol (2014)

Bottom Line: Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Hospital & Institute, Tianjin, 30060, PR China. yangjilong@tjmuch.com.

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.

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Related in: MedlinePlus

Transcriptome sequencing of 11 osteosarcomas revealed two hotspots of chromosomal rearrangement. One hotspot in 17p was associated with TP53-disrupting rearrangements. The second hotspot in 12q was associated with MDM2/CDK4 co-amplification.
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Fig1: Transcriptome sequencing of 11 osteosarcomas revealed two hotspots of chromosomal rearrangement. One hotspot in 17p was associated with TP53-disrupting rearrangements. The second hotspot in 12q was associated with MDM2/CDK4 co-amplification.

Mentions: Fusion gene detection based on transcriptome sequencing identified a total of 16 fusion genes in our cohort of 11 osteosarcomas. 7 of 11 osteosarcomas harbored at least one fusion gene (Additional file 1: Figure S2, Tables S1 and S2). We identified a pattern of interchromosomal gene fusions clustered at two hotspots in the genome (FigureĀ 1). The first hotspot, rearranged in two osteosarcomas (samples 1 and 6-2), coincided with the TP53 tumor suppressor gene in 17p. Sample 6-2 harbored a fusion between TP53 and cyclinB1(CCNB1), while sample 1 had TP53 juxtaposed with the non-coding gene AC016582.2, whose biological function is unknown. Both fusions disrupted TP53 between exons 1 and 2, preventing the production of p53 protein from one allele (Additional file 1: Figure S3). Based on the fusion transcript structure, neither TP53 rearrangement is expected to produce chimeric protein.Figure 1


Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma.

Yang J, Annala M, Ji P, Wang G, Zheng H, Codgell D, Du X, Fang Z, Sun B, Nykter M, Chen K, Zhang W - J Hematol Oncol (2014)

Transcriptome sequencing of 11 osteosarcomas revealed two hotspots of chromosomal rearrangement. One hotspot in 17p was associated with TP53-disrupting rearrangements. The second hotspot in 12q was associated with MDM2/CDK4 co-amplification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197299&req=5

Fig1: Transcriptome sequencing of 11 osteosarcomas revealed two hotspots of chromosomal rearrangement. One hotspot in 17p was associated with TP53-disrupting rearrangements. The second hotspot in 12q was associated with MDM2/CDK4 co-amplification.
Mentions: Fusion gene detection based on transcriptome sequencing identified a total of 16 fusion genes in our cohort of 11 osteosarcomas. 7 of 11 osteosarcomas harbored at least one fusion gene (Additional file 1: Figure S2, Tables S1 and S2). We identified a pattern of interchromosomal gene fusions clustered at two hotspots in the genome (FigureĀ 1). The first hotspot, rearranged in two osteosarcomas (samples 1 and 6-2), coincided with the TP53 tumor suppressor gene in 17p. Sample 6-2 harbored a fusion between TP53 and cyclinB1(CCNB1), while sample 1 had TP53 juxtaposed with the non-coding gene AC016582.2, whose biological function is unknown. Both fusions disrupted TP53 between exons 1 and 2, preventing the production of p53 protein from one allele (Additional file 1: Figure S3). Based on the fusion transcript structure, neither TP53 rearrangement is expected to produce chimeric protein.Figure 1

Bottom Line: Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Hospital & Institute, Tianjin, 30060, PR China. yangjilong@tjmuch.com.

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.

Show MeSH
Related in: MedlinePlus