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Updated: Apr 28, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
The genetic basis for inactivation of Wnt pathway in human osteosarcoma
Xiaoling Du, Jilong Yang1, Da Yang
1Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 30060, China. yangjilong@tjmuch.com.
Background:
Osteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma.
Methods:
aCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, β-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples.
Results:
KEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no β-catenin protein was detected in the nucleus. β-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall survival of human osteosarcoma patients.
Conclusions:
Frequent deletions of Wnt and other Wnt signaling pathway genes suggest that the Wnt signaling pathway is genetically inactivated in human osteosarcoma.
Insights
Osteosarcoma frequently shows genetic alterations in the Wnt signaling pathway, leading to its inactivation. WNT1-negative patients with osteosarcoma may have better disease-free survival, especially if cyclin D1 is also negative.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osteosarcoma is a genetically unstable bone cancer with a poor prognosis.
- Understanding pathway alterations is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the systemic pathway alterations in osteosarcoma using integrated genomic and transcriptomic analyses.
- To identify the role of the Wnt signaling pathway in osteosarcoma development and progression.
Main Methods:
- Microarray-based comparative genomic hybridization (aCGH) and transcriptome sequencing (RNA-seq) were performed on osteosarcoma samples.
- Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified recurrent copy number changes and altered pathways.
- Protein expression of Wnt pathway components (WNT1, β-catenin, c-myc, cyclin D1) was assessed by immunohistochemistry (IHC).
Main Results:
- Frequent deletions of Wnt signaling pathway genes were identified.
- Reduced mRNA expression of Wnt pathway transcripts was observed.
- While WNT1 protein was present, nuclear β-catenin was absent in osteosarcoma samples. WNT1-negative patients showed a trend towards longer disease-free survival, particularly when cyclin D1 was also negative.
Conclusions:
- The Wnt signaling pathway appears to be genetically inactivated in human osteosarcoma.
- Wnt pathway alterations may serve as potential prognostic markers for osteosarcoma patients.
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