Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous

Difilippo, Valeria; Saba, Karim H.; Styring, Emelie; Magnusson, Linda; Nilsson, Jenny; Nathrath, Michaela; Baumhoer, Daniel; Nord, Karolin H.

doi:10.1016/j.labinv.2023.100283

Cited by 3 publications

(1 citation statement)

References 56 publications

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“…The overall five-year survival rate is approximately 65% for patients with local OS and only 20% for patients with metastatic OS [ 25 ]. The challenging nature of OS treatment arises from its impact on diverse patient populations and the complex genetic alterations involved [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma

Zheng,

Cheng,

et al. 2024

Aging

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Background: Osteosarcoma (OS) is a primary malignant bone tumor arising from mesenchymal cells. The standard clinical treatment for OS involves extensive tumor resection combined with neoadjuvant chemotherapy or radiotherapy. OS's invasiveness, lung metastasis, and drug resistance contribute to a low cure rate and poor prognosis with this treatment. Metallothionein 1G (MT1G), observed in various cancers, may serve as a potential therapeutic target for OS. Methods: OS samples in GSE33382 and TARGET datasets were selected as the test cohorts. As the external validation cohort, 13 OS tissues and 13 adjacent cancerous tissues from The Second Affiliated Hospital of Nanchang University were collected. Patients with OS were divided into high and low MT1G mRNA-expression groups; differentially expressed genes (DEGs) were identified as MT1G-related genes. The biological function of MT1G was annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and gene set enrichment analysis (GSEA). Gene expression correlation analysis and competing endogenous RNA (ceRNA) regulatory network construction were used to determine potential biological regulatory relationships of DEGs. Survival analysis assessed the prognostic value of MT1G. Results: MT1G expression increased in OS samples and presented higher in metastatic OS compared with non-metastatic OS. Functional analyses indicated that MT1G was mainly associated with spliceosome. A ceRNA network with DEGs was constructed. MT1G is an effective biomarker predicting survival and correlated with increased recurrence rates and poorer survival. Conclusions: This research identified MT1G as a potential biomarker for OS prognosis, highlighting its potential as a therapy target.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma

Zheng,

Cheng,

et al. 2024

Aging

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CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma

Saba,

Difilippo,

Styring

et al. 2024

npj Genom. Med.

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Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We discerned four major subgroups, ranging from nearly intact genomes to heavily rearranged ones, each harbouring CDK4 and MDM2 amplification or CDK4 amplification with TP53 structural alterations. While amplicons involving MDM2 exhibited signs of an initial chromothripsis event, no evidence of chromothripsis was found in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus led to co-amplification of the CDK4 locus. Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.

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CDK4is co-amplified with eitherTP53promoter gene fusions orMDM2through distinct mechanisms in osteosarcoma

Saba,

Difilippo,

Styring

et al. 2024

Preprint

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Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We identified four major subgroups: (i) low-grade osteosarcoma with chromosome 12 amplicons as the sole acquired alteration, (ii) high- and low-grade tumours with CDK4 and MDM2 amplification along with few changes affecting other chromosomes, (iii) high-grade osteosarcomas with heavily rearranged genomes including either CDK4 and MDM2 amplification or (iv) CDK4 amplification and TP53 structural alterations. The amplicons involving MDM2 exhibited signs of an initial chromothripsis event affecting chromosome 12. In contrast, there was no indication of a chromothripsis event on chromosome 12 in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus resulted in breakage and repair processes that co-amplified the CDK4 locus. Furthermore, our investigation revealed recurring promoter swapping events that involved the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events led to the ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions, respectively, in two distinct cases.

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Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous

Cited by 3 publications

References 56 publications

Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma

Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma

CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma

CDK4is co-amplified with eitherTP53promoter gene fusions orMDM2through distinct mechanisms in osteosarcoma

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