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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.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.Our study represents the first whole transcriptome analysis of untreated human osteosarcoma.

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

Recurrent TP53 pathway alterations in human osteosarcoma. (A) Activating (red) and inactivating (blue) alterations in the p53 and RB1 pathways identified in our cohort. (B) Samples 8, 9, 10 harbored 12q co-amplification of CDK4 and MDM2. 12q amplification was mutually exclusive with alterations in the TP53 gene. (C) Matrix of genetic alterations observed in our cohort. Nine of 11 patients harbored disrupting alterations in the TP53 pathway genes.
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Fig2: Recurrent TP53 pathway alterations in human osteosarcoma. (A) Activating (red) and inactivating (blue) alterations in the p53 and RB1 pathways identified in our cohort. (B) Samples 8, 9, 10 harbored 12q co-amplification of CDK4 and MDM2. 12q amplification was mutually exclusive with alterations in the TP53 gene. (C) Matrix of genetic alterations observed in our cohort. Nine of 11 patients harbored disrupting alterations in the TP53 pathway genes.

Mentions: The second hotspot, located in 12q, was rearranged in four osteosarcomas (samples 1, 8, 9, 10) and coincided with the genes MDM2 and CDK4 (Figure 1). MDM2 and CDK4 are known to be frequently co-amplified in osteosarcoma and contribute to suppression of the p53 and RB1 pathways (Figure 2A) [12-14]. A strong localized gene dosage effect was observed in three of the four 12q-rearranged cases (samples 8, 9 and 10), suggesting that fusion genes in this locus often arise as a by-product of MDM2/CDK4 co-amplification (Figure 2B). Many of the 12q fusion genes produced chimeric proteins or disrupted cancer-associated genes such as RUNX2, CCND3, and LRP1, indicating that some of the fusions may contribute to cancer progression independently of MDM2/CDK4 co-amplification.Figure 2


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)

Recurrent TP53 pathway alterations in human osteosarcoma. (A) Activating (red) and inactivating (blue) alterations in the p53 and RB1 pathways identified in our cohort. (B) Samples 8, 9, 10 harbored 12q co-amplification of CDK4 and MDM2. 12q amplification was mutually exclusive with alterations in the TP53 gene. (C) Matrix of genetic alterations observed in our cohort. Nine of 11 patients harbored disrupting alterations in the TP53 pathway genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Recurrent TP53 pathway alterations in human osteosarcoma. (A) Activating (red) and inactivating (blue) alterations in the p53 and RB1 pathways identified in our cohort. (B) Samples 8, 9, 10 harbored 12q co-amplification of CDK4 and MDM2. 12q amplification was mutually exclusive with alterations in the TP53 gene. (C) Matrix of genetic alterations observed in our cohort. Nine of 11 patients harbored disrupting alterations in the TP53 pathway genes.
Mentions: The second hotspot, located in 12q, was rearranged in four osteosarcomas (samples 1, 8, 9, 10) and coincided with the genes MDM2 and CDK4 (Figure 1). MDM2 and CDK4 are known to be frequently co-amplified in osteosarcoma and contribute to suppression of the p53 and RB1 pathways (Figure 2A) [12-14]. A strong localized gene dosage effect was observed in three of the four 12q-rearranged cases (samples 8, 9 and 10), suggesting that fusion genes in this locus often arise as a by-product of MDM2/CDK4 co-amplification (Figure 2B). Many of the 12q fusion genes produced chimeric proteins or disrupted cancer-associated genes such as RUNX2, CCND3, and LRP1, indicating that some of the fusions may contribute to cancer progression independently of MDM2/CDK4 co-amplification.Figure 2

Bottom Line: 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.Our study represents the first whole transcriptome analysis of untreated human osteosarcoma.

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