The genetics of osteosarcoma

Abstract

Osteosarcoma is a primary bone malignancy with a particularly high incidence rate in children and adolescents relative to other age groups. The etiology of this often aggressive cancer is currently unknown, because complicated structural and numeric genomic rearrangements in cancer cells preclude understanding of tumour development. In addition, few consistent genetic changes that may indicate effective molecular therapeutic targets have been reported. However, high-resolution techniques continue to improve knowledge of distinct areas of the genome that are more commonly associated with osteosarcomas. Copy number gains at chromosomes 1p, 1q, 6p, 8q, and 17p as well as copy number losses at chromosomes 3q, 6q, 9, 10, 13, 17p, and 18q have been detected by numerous groups, but definitive oncogenes or tumour suppressor genes remain elusive with respect to many loci. In this paper, we examine studies of the genetics of osteosarcoma to comprehensively describe the heterogeneity and complexity of this cancer.

Figure 1

Frequent chromosomal aberrations in sporadic conventional osteosarcoma. Green highlighted areas represent minimal common regions of gain and amplification, or cytobands containing frequently gained and amplified genes. Red highlighted areas represent minimal common regions of loss, or cytobands containing genes frequently lost. Refer to Table 1 and the text for more details regarding minimal common regions and the presence of genetic mutations in some areas of the genome. Chromosome images adapted from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman/. Accessed January 25, 2012).

Figure 2

Chromosome 6p rearrangement. Chromosome 6p12-p21, which contains RUNX2, frequently undergoes complex rearrangements in osteosarcoma and is one example of a distinct genomic locus that undergoes such alterations in this cancer. In this case, there is gain and amplification of the labeled genes (with wide variation between cells) as shown in the image of interphase fluorescence in situ hybridisation (FISH) for chromosome 6p. The FISH experiment employed probes for FBXO9 (yellow), RUNX2 (orange), PIM1 (green), E2F3 (red), and the centromere of chromosome 6 (light blue). The RUNX2 immunohistochemistry (IHC) image was obtained after staining for RUNX2 protein. High levels of the protein were nearly ubiquitous in the nuclei of cells and were associated with genetic amplification of RUNX2. The FISH and IHC images were obtained via experiments performed on serial formalin-fixed paraffin-embedded sections of one osteoblastic (conventional) osteosarcoma tissue specimen. MSC, mesenchymal stem cell.