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Miwa, S. Biomarkers in Chondrosarcoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/19299 (accessed on 01 April 2026).
Miwa S. Biomarkers in Chondrosarcoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/19299. Accessed April 01, 2026.
Miwa, Shinji. "Biomarkers in Chondrosarcoma" Encyclopedia, https://encyclopedia.pub/entry/19299 (accessed April 01, 2026).
Miwa, S. (2022, February 10). Biomarkers in Chondrosarcoma. In Encyclopedia. https://encyclopedia.pub/entry/19299
Miwa, Shinji. "Biomarkers in Chondrosarcoma." Encyclopedia. Web. 10 February, 2022.
Biomarkers in Chondrosarcoma
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23031096

Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including IDH1/2, COL2A1, and PD-L1. In addition, several molecule-targeting agents and immunotherapy have shown favorable antitumor activities in clinical studies of patients with advanced chondrosarcoma.

Anticancer Chondrosarcoma Biomarkers

1. Gene Mutations in Chondrosarcoma

Most chondrosarcomas are resistant to anticancer agents; therefore, identifying new therapeutic targets in chondrosarcoma is crucial. Gene mutations in chondrosarcomas can be helpful in investigating new therapeutic approaches and prognostic factors. Associations of several gene mutations with chondrosarcoma progression have been reported [1][2][3][4][5]. Chondrosarcomas frequently have gene mutations of isocitrate dehydrogenase 1/2 (IDH1/2), followed by collagen type II alpha 1 chain (COL2A1) and TP53.
IDH, an NADP+-dependent enzyme, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the Krebs cycle. IDH1 exists in the cytoplasm, and IDH2 exists in the mitochondria. IDH1/2 mutations are characteristic gene mutations that are detected in approximately 50% of chondrosarcomas and central and periosteal cartilaginous tumors [2]. These mutations result in the accumulation of 2-hydroxyglutarate (2HG), an oncometabolite [6][7]. Increased production of 2HG inhibits ten-eleven translocation (TET) enzymes, resulting in excessive methylation of DNA at CpG islands, and the regions of CpG island hypermethylation are enriched for genes related to stem cell maintenance, differentiation, and lineage specification [8]. Lu et al. reported that the expression of mutant IDH2 caused DNA hypermethylation and impaired differentiation in murine 10T1/2 mesenchymal progenitor cells, the generation of undifferentiated sarcomas, and the hypermethylation and impairment in differentiation could be reversed by treatment with DNA hypomethylating agents [8]. In contrast, the influence of IDH mutations on tumorigenesis and progression in chondrosarcoma is controversial [9][10][11]. Li et al. reported that the IDH1 inhibitor AGI-5198 decreased oncometabolite D-2-hydroxyglutarate (D-2-HG), inhibited proliferation and migration, and induced apoptosis in chondrosarcoma cells [10]. In contrast, Suijker et al. reported that AGI-5198 dose-dependently decreased D-2-HG levels, although the study showed no significant influence on proliferation and migration [11].
Mutations of the major cartilage collagen gene COL2A1, with deletions, insertions, and rearrangements, were identified in 37% of chondrosarcomas [3]. The patterns of mutations suggest impairments in normal collagen biosynthesis in chondrosarcoma [3]. These mutations cause impairment of fundamental extracellular matrix (ECM) deposition and signaling, which may contribute to tumorigenesis by inhibiting normal cartilage differentiation [3]. Furthermore, the study showed mutations in TP53 (20%), the RB1 pathway (33%), and Hedgehog signaling (18%) in chondrosarcoma [3].
TP53 mutations are among the most frequently observed mutations in human cancers [12][13]. TP53 mutations are observed in 20–50% of conventional chondrosarcomas and dedifferentiated chondrosarcomas [14][3][15][16][17]. Oshiro et al. reported a strong correlation between TP53 mutations and metastatic disease or histological grade of chondrosarcoma [15]. Loss of function in p53 may play an important role in the progression of chondrosarcoma and transformation to highly malignant chondrosarcomas [18][19][20].
Deletions in tuberous sclerosis 1 (TSC1) and phosphatase and tensin homolog (PTEN) genes and nonsense and missense mutations in the protein patched homolog 1 (PTCH1) have been observed in central chondrosarcomas [3][21]. Mutations in exostosin glycosyltransferase 1/2 (EXT1/2) genes, which participate in the differentiation of chondrocytes, have been observed in peripheral chondrosarcomas [3][19]. In a study using gene expression profiles obtained from the Gene Expression Omnibus database, differentially expressed genes between enchondromas and chondrosarcomas were investigated [4]. In this study, upregulated genes were related to epithelial–mesenchymal transition and the VEGF signaling pathway. The expression levels of four genes (MFAP2, GOLM1, STMN1, and HN1) increased continuously from control, enchondroma, to chondrosarcoma, and the expression of two genes (CAB39L and GAB2) decreased.
Although low levels of the tumor mutational burden (TMB) have been reported in chondrosarcoma [21], TMB is associated with histological grades. Grades 2 and 3 and dedifferentiated chondrosarcomas have levels of somatic mutations more than two times higher than grade 1 chondrosarcoma [3].

2. Biomarkers in Chondrosarcoma

The identification of biomarkers is beneficial in the management of malignancies because of various applications, including screening, differential diagnosis, the prediction of prognosis, and the monitoring of tumor progression. Several candidates of biomarkers for chondrosarcoma have been reported [22][23]. Mutations in IDH1/2 have been considered biomarkers for acute myeloid leukemia and glioma [24][25]. In chondrosarcomas, Ollier disease, and Maffucci syndrome, a high incidence of IDH1 and IDH2 mutations has been reported [26]. In a meta-analysis of 488 patients with chondrosarcoma, IDH1 and IDH2 mutations were detected in 39% and 12% of patients, respectively [27]. In the study, IDH1/2 mutations were correlated with age, origin, histological grade, tumor diameter, relapse, and mortality, and multivariate analysis revealed a significant association between IDH1/2 mutations and poor overall survival. Nakagawa et al. investigated the correlation between IDH mutations and clinical outcomes in chondrosarcoma [28]. In the study, 15 (39%) of 38 patients had IDH1 mutations, and 5 (13%) of 38 patients showed IDH2 mutations. The study showed that IDH mutation was associated with worse overall survival, and IDH mutation was a significantly poor prognostic factor in univariate and multivariate analyses.
Giordano et al. investigated the expression of Eph type-A receptor (EphA2), a key oncoprotein implicated in angiogenesis, self-renewal, and metastasis, in bone sarcoma [29]. In the study, tumor tissues of osteosarcoma, Ewing sarcoma, and chondrosarcoma showed higher expression of EphA2 compared to normal tissues. Furthermore, the EphA2 inhibitor showed significant antitumor effects in patient-derived bone sarcoma cells. These data suggest that EphA2 is a potential therapeutic target in bone sarcoma, including chondrosarcoma.
Small ubiquitin-like modifier (SUMO), which is covalently attached to target proteins as a post-translational modification to alter the stability, localization, and function of the protein, can be a potential biomarker and therapeutic target in patients with chondrosarcoma. Kroonen et al. investigated the correlation between the expression of SUMO and clinical outcomes in patients with chondrosarcoma [30]. They reported that higher expressions of SUMO1 and SUMO2/3 were associated with an increased histological grade, and that a high expression of SUMO2/3 correlated with poor overall survival (OS). Furthermore, the SUMO E1 inhibitor ML792 reduced the cell proliferation and viability of chondrosarcoma cell lines in vitro. These results suggest that SUMO may be a potential therapeutic target in chondrosarcoma.
Takeuchi et al. investigated the expression of the receptor for endogenous secretory advanced glycation endproducts (esRAGE) and its ligand, high-mobility group box-1 (HMGB1), and their association with the histological grade in cartilaginous tumors [31]. In this study, the expression of esRAGE and HMGB1 was associated with the histological grade. Furthermore, the expression of esRAGE was associated with tumor recurrence, lung metastasis, and poor survival in patients with grade 1 chondrosarcoma. The results of the study suggest that esRAGE can be used as a biomarker to predict the histological grade and prognosis in patients with chondrosarcomas.
High expressions of the aurora kinases, which belong to the family of serine and threonine kinases, have been reported in several malignant tumors [32]. Liang et al. reported high expressions of aurora kinase A and B in high-grade chondrosarcoma compared to low-grade chondrosarcoma, and reported that the expression of aurora kinase correlated with worse survival in patients with chondrosarcomas [33].
Hypoxia-inducible factor (HIF) is an important transcription factor that contributes to cellular responses to hypoxic conditions, tumor survival, proliferation, and progression [34]. Chen et al. reported a high expression of HIF-2α in chondrosarcoma tissues compared to normal tissues [35]. In this study, the level of Beclin 1, a key mediator of autophagy, was significantly more decreased in chondrosarcoma tissues compared to normal tissues. HIF-2α and Beclin 1 had a significant inverse relationship with the prognosis in patients with chondrosarcoma. In another study, a high expression of HIF-1α was observed in patients with chondrosarcomas, and the increased expressions of HIF-1α were correlated with higher histological grades and clinical outcomes [36]. These findings suggest that HIF may be a prognostic predictor in patients with chondrosarcoma.
Rozeman LB et al. investigated the association between the expression of several molecules, including cyclin D1, p53, and plasminogen activator inhibitor 1 (PAI-1), with the patient survival [23]. In this study, the expression of PAI-1 correlated with better survival in patients with dedifferentiated peripheral chondrosarcomas.
The Hedgehog signaling pathway regulates cell proliferation during embryogenesis. Tiet et al. reported high expressions of Hedgehog target genes PTCH1 and GLI1 in chondrosarcomas, and that Hedgehog protein increased the cell proliferation of chondrosarcoma, and inhibitors of Hedgehog signaling decreased the proliferation [22].
Parafioriti et al. investigated the associations between miRNA and miRNA-regulated pathways with tumorigenesis in chondrosarcoma grades 1–3 [37]. While all grades showed similar expression profiles of miRNA, including miR-140-3p, significantly different expression profiles of miRNA were observed between grade 1 and grade 2/3 chondrosarcomas. The study suggests the contribution of miRNAs and their target pathway to the progression of chondrosarcoma.
In a study using multi-omics molecular profiles of chondrosarcoma, the acquisition of a proliferative state, the silencing of the 14q32 imprinted locus, and DNA methylation of IDH mutations were important to predict the histological malignancy and the clinical outcome [38]. Furthermore, a multi-omics classification, established by combining these molecular characteristics, was highly associated with OS in patients with chondrosarcoma.
Shi et al. investigated the association of DNA methylation and the transcription of immune-related genes with changes in the tumor microenvironment and the prognosis in patients with osteosarcoma [39]. In the study, immune-related DNA methylation patterns (IMPs), clinical outcomes, and tumor microenvironment characteristics in the patients were investigated, and an IMP-associated scoring model was constructed and evaluated in an independent patient cohort. The model may enable the prediction of prognosis and potential rationale for targeted therapy and immunotherapy in osteosarcoma. Studies on IMP-related scoring models for chondrosarcoma are sought to predict patient survival and therapeutic responses.

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