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Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy.

Sadikovic B, Thorner P, Chilton-Macneill S, Martin JW, Cervigne NK, Squire J, Zielenska M - BMC Cancer (2010)

Bottom Line: Recent discoveries have highlighted a potential role of a number of genes including: RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, P53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L.RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed, and DOCK5, CDKN1A, RB1, P53, and LSAMP showed significant loss of expression relative to normal osteoblasts.In addition to being overexpressed in osteosarcoma tumor samples relative to normal osteoblasts, RUNX2 was the only gene of the 16 to show significant overexpression in tumors that had a poor response to chemotherapy relative to good responders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Richardson Labs, Queen's University, Kingston, K7L 3N6 Canada.

ABSTRACT

Background: Human osteosarcoma is the most common pediatric bone tumor. There is limited understanding of the molecular mechanisms underlying osteosarcoma oncogenesis, and a lack of good diagnostic as well as prognostic clinical markers for this disease. Recent discoveries have highlighted a potential role of a number of genes including: RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, P53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L.

Methods: Our objective was to assess relative expression levels of these 16 genes as potential biomarkers of osteosarcoma oncogenesis and chemotherapy response in human tumors. We performed quantitative expression analysis in a panel of 22 human osteosarcoma tumors with differential response to chemotherapy, and 5 normal human osteoblasts.

Results: RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed, and DOCK5, CDKN1A, RB1, P53, and LSAMP showed significant loss of expression relative to normal osteoblasts. In addition to being overexpressed in osteosarcoma tumor samples relative to normal osteoblasts, RUNX2 was the only gene of the 16 to show significant overexpression in tumors that had a poor response to chemotherapy relative to good responders.

Conclusion: These data underscore the loss of tumor suppressive pathways and activation of specific oncogenic mechanisms associated with osteosarcoma oncogenesis, while drawing attention to the role of RUNX2 expression as a potential biomarker of chemotherapy failure in osteosarcoma.

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Expression analysis of osteosarcoma-related genes. qRT-PCR levels of gene expression of 16 osteosarcoma-related genes in 5 normal human osteoblasts and 22 human osteosarcoma samples are shown on y-axis. The samples are grouped based on the response to chemotherapy status on y-axis. Corresponding box and whiskers plots representing the mean, 25th and 75th percentile (boxes), and 10th and 90th percentile (whiskers) are also shown. From left to right, and top to bottom of the panel, the plots are placed in the order of Mann-Whitney p-value significance (tumor vs. normal). HOB: normal human osteoblasts; Good: Favorable response to chemotherapy (Huvos grades III and IV); Poor: Unfavorable response to chemotherapy (Huvos grades I and II).
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Figure 1: Expression analysis of osteosarcoma-related genes. qRT-PCR levels of gene expression of 16 osteosarcoma-related genes in 5 normal human osteoblasts and 22 human osteosarcoma samples are shown on y-axis. The samples are grouped based on the response to chemotherapy status on y-axis. Corresponding box and whiskers plots representing the mean, 25th and 75th percentile (boxes), and 10th and 90th percentile (whiskers) are also shown. From left to right, and top to bottom of the panel, the plots are placed in the order of Mann-Whitney p-value significance (tumor vs. normal). HOB: normal human osteoblasts; Good: Favorable response to chemotherapy (Huvos grades III and IV); Poor: Unfavorable response to chemotherapy (Huvos grades I and II).

Mentions: In order to quantitatively assess the expression of the target genes (RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, TP53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L) we performed qRT-PCR on the tumor cohort and human osteoblast samples (Additional file 1). Statistical analysis of these data revealed significant changes in a number of genes (Table 2). Tumors displayed significant overexpression of RECQL4, SPP1, RUNX2, and IBSP genes and loss of expression of DOCK5, CDKN1A, RB1, TP53, and LSAMP (p < 0.05) (Figure 1). The highest level of overexpression was measured in SPP1 with 113-fold overexpression, while the largest reduction of expression of 36-fold was evident in the DOCK5 gene. Comparison of tumors with unfavorable response to ch emotherapy to favorable responders revealed RUNX2 as the only significant gene (p = 0.03). On average unfavorable responders to chemotherapy showed 3.3-fold increase in the RUNX2 gene expression relative to favorable responders. Furthermore, RUNX2 expression showed a trend towards overexpression going from normal osteoblasts to favorable responders to chemotherapy and then to unfavorable responders to chemotherapy (Figure 1). The tumor sample #256 that exhibited the worst response to chemotherapy, also showed highest levels (113-fold) of RUNX2 overexpression (Additional file 1).


Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy.

Sadikovic B, Thorner P, Chilton-Macneill S, Martin JW, Cervigne NK, Squire J, Zielenska M - BMC Cancer (2010)

Expression analysis of osteosarcoma-related genes. qRT-PCR levels of gene expression of 16 osteosarcoma-related genes in 5 normal human osteoblasts and 22 human osteosarcoma samples are shown on y-axis. The samples are grouped based on the response to chemotherapy status on y-axis. Corresponding box and whiskers plots representing the mean, 25th and 75th percentile (boxes), and 10th and 90th percentile (whiskers) are also shown. From left to right, and top to bottom of the panel, the plots are placed in the order of Mann-Whitney p-value significance (tumor vs. normal). HOB: normal human osteoblasts; Good: Favorable response to chemotherapy (Huvos grades III and IV); Poor: Unfavorable response to chemotherapy (Huvos grades I and II).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875220&req=5

Figure 1: Expression analysis of osteosarcoma-related genes. qRT-PCR levels of gene expression of 16 osteosarcoma-related genes in 5 normal human osteoblasts and 22 human osteosarcoma samples are shown on y-axis. The samples are grouped based on the response to chemotherapy status on y-axis. Corresponding box and whiskers plots representing the mean, 25th and 75th percentile (boxes), and 10th and 90th percentile (whiskers) are also shown. From left to right, and top to bottom of the panel, the plots are placed in the order of Mann-Whitney p-value significance (tumor vs. normal). HOB: normal human osteoblasts; Good: Favorable response to chemotherapy (Huvos grades III and IV); Poor: Unfavorable response to chemotherapy (Huvos grades I and II).
Mentions: In order to quantitatively assess the expression of the target genes (RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, TP53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L) we performed qRT-PCR on the tumor cohort and human osteoblast samples (Additional file 1). Statistical analysis of these data revealed significant changes in a number of genes (Table 2). Tumors displayed significant overexpression of RECQL4, SPP1, RUNX2, and IBSP genes and loss of expression of DOCK5, CDKN1A, RB1, TP53, and LSAMP (p < 0.05) (Figure 1). The highest level of overexpression was measured in SPP1 with 113-fold overexpression, while the largest reduction of expression of 36-fold was evident in the DOCK5 gene. Comparison of tumors with unfavorable response to ch emotherapy to favorable responders revealed RUNX2 as the only significant gene (p = 0.03). On average unfavorable responders to chemotherapy showed 3.3-fold increase in the RUNX2 gene expression relative to favorable responders. Furthermore, RUNX2 expression showed a trend towards overexpression going from normal osteoblasts to favorable responders to chemotherapy and then to unfavorable responders to chemotherapy (Figure 1). The tumor sample #256 that exhibited the worst response to chemotherapy, also showed highest levels (113-fold) of RUNX2 overexpression (Additional file 1).

Bottom Line: Recent discoveries have highlighted a potential role of a number of genes including: RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, P53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L.RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed, and DOCK5, CDKN1A, RB1, P53, and LSAMP showed significant loss of expression relative to normal osteoblasts.In addition to being overexpressed in osteosarcoma tumor samples relative to normal osteoblasts, RUNX2 was the only gene of the 16 to show significant overexpression in tumors that had a poor response to chemotherapy relative to good responders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Molecular Medicine, Richardson Labs, Queen's University, Kingston, K7L 3N6 Canada.

ABSTRACT

Background: Human osteosarcoma is the most common pediatric bone tumor. There is limited understanding of the molecular mechanisms underlying osteosarcoma oncogenesis, and a lack of good diagnostic as well as prognostic clinical markers for this disease. Recent discoveries have highlighted a potential role of a number of genes including: RECQL4, DOCK5, SPP1, RUNX2, RB1, CDKN1A, P53, IBSP, LSAMP, MYC, TNFRSF1B, BMP2, HISTH2BE, FOS, CCNB1, and CDC5L.

Methods: Our objective was to assess relative expression levels of these 16 genes as potential biomarkers of osteosarcoma oncogenesis and chemotherapy response in human tumors. We performed quantitative expression analysis in a panel of 22 human osteosarcoma tumors with differential response to chemotherapy, and 5 normal human osteoblasts.

Results: RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed, and DOCK5, CDKN1A, RB1, P53, and LSAMP showed significant loss of expression relative to normal osteoblasts. In addition to being overexpressed in osteosarcoma tumor samples relative to normal osteoblasts, RUNX2 was the only gene of the 16 to show significant overexpression in tumors that had a poor response to chemotherapy relative to good responders.

Conclusion: These data underscore the loss of tumor suppressive pathways and activation of specific oncogenic mechanisms associated with osteosarcoma oncogenesis, while drawing attention to the role of RUNX2 expression as a potential biomarker of chemotherapy failure in osteosarcoma.

Show MeSH
Related in: MedlinePlus