Molecular diagnosis of osteosarcoma: A review

Osteosarcoma (OS) is the third most common tumor in children and adolescents, with a second peak of incidence after the fifth decade of life. The annual mortality rate of OS is approximately ۴.۴ per million, and the prognosis depends mainly on the status of metastasis to the lungs. Due to the highly metastatic nature of OS, lung metastases were reported in around ۱۵-۲۰% of newly diagnosed cases, and about ۶۰% of patients suffer from micro-metastases. Recently, technology and data analysis methods have provided more efficient diagnostic approaches, leading to the identification of novel biomarkers for OS prognosis and diagnosis. Therefore, we reviewed and summarized the molecular diagnosis of osteosarcoma. Methods: Several databases, including Google Scholar, PubMed, Science Direct, Web of Science, Scopus, etc., were searched. Using the terms "osteosarcoma" and “molecular diagnosis”, relevant articles published since ۲۰۲۰ were selected and reviewed. Results: OS is composed of a complex signaling network involving numerous molecules and genes. Alkaline phosphatase (AKP) and lactase dehydrogenase (LDH) have been identified as non-specific OS biomarkers. MicroRNAs (miRNA) have also been reported as favorable signatures for the early detection of metastatic OS. The EGF-containing fibulin extracellular matrix protein ۱ (EFEMP۱) gene is reportedly associated with OS invasion and poor prognosis. The ۵-methylcytosine (m۵C), an epigenetic amplification, plays a crucial role in the diagnosis and prognosis of OS. The X-ray repair cross-complementing ۶ (XRCC۶) gene has also been reported to be involved in the poor prognosis of OS. In one study, almost ۲۰% of the harbored tumors had a chromosome ۴q۱۲ amplification. Another study reported vascular endothelial growth factor A (VEGFA) gene amplification in ۳۲ out of ۵۰ OS patients. Zinc finger antisense ۱ (ZFAS۱) level was also elevated in OS cases. Matriline ۴ (MATN۴), a member of the extracellular matrix proteins, interferon-induced transmembrane protein ۵ (IFITM۵), and pannexin۳ overexpression were observed in OS. Matrix metallopeptidase ۱۳ (MMP۱۳) is also a known gene that promotes the invasion and progression of OS by forming a network with other MMPs. HBA۱, HBA۲, and HBB, genes encoding hemoglobin subunits, were downregulated in OS samples. Among signaling pathways, JAK/STAT۳ was identified as an essential regulator of OS cell proliferation and apoptosis. Its inappropriate activation in OS has been linked to physiological events such as metastasis. OS cell lines highly express STAT۳, whose inhibition can prevent the proliferative ability of OS cells. Conclusion: Osteosarcoma accounts for ۳-۶ % of childhood cancers and less than ۱% of adult cancers. In recent years, molecular profiling of tumors by next-generation sequencing and developing new practical modalities have increased our knowledge of the OS. Sequencing of the tumor DNA has revealed mutations clustered in the mucin, human leukocyte antigen (HLA), zinc finger and DNA repair, etc, in addition to signaling pathways such as Wnt, JAK/ STAT۳, Hippo, Notch, and NF-κB, etc. Unfortunately, because of the high chromosomal instability and unusually complicated karyotypes, none of these candidate biomarkers for OS diagnosis are widely used for clinical purposes. Therefore, further research to identify specific biomarkers would be essential.

کلیدواژه ها:

Osteosarcoma ، molecular diagnosis ، next generation sequencing ، signaling pathways