Molecular Biology of Osteosarcoma

Abstract

Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond-Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK-ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.

Keywords: molecular imaging; molecular mechanisms; osteosarcoma; targeted therapy; theranostics; tumor initiating cells.

Figure 1

Schematic representation of the genomic locus of the TP53 gene and its protein sequence with marked gene alterations present in osteosarcoma patients derived samples. (Panel A) represents mutations (●), deletions (■) and translocations (∆) locations in particular introns. Roman numerals refer to introns, Arabic numerals refer to exons. (Panel B) represents p53 protein primary structure with marked domains and amino acids number of mutations (indels, missense, nonsense). TAD—transactivation domain; Pro—proline-rich region; DNA binding—core domain which can bind DNA; oligomerization—oligomerization domain. Based on data from [17,18,29,62,63].

Figure 2

Schematic representation of changes after chromothripsis (Panel A) and kataegis (Panel B). The occurrence of chromothripsis results in a new configuration in the part of a chromosome. Kataegis describes a hypermutation pattern located in one or multiple loci in the genome.

Figure 3

Overview of molecular markers of osteosarcoma tumor initiating cells.