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.
Osteosarcoma is the most common primary bone malignancy, with a high incidence rate in children and adolescents compared to other age groups. Tumours most often arise in the long bones from osteoid-producing neoplastic cells adjacent to the growth plates, occurring less commonly in the axial skeleton and other nonlong bones [
Decades’ worth of molecular cytogenetics studies and genomic analyses of osteosarcomas have been completed through karyotyping, comparative genomic hybridisation (CGH), fluorescence
In this paper, we have collected studies of the genetics of osteosarcoma to illustrate the heterogeneity and complexity of this tumour type at the level of the chromosome and gene. Osteosarcoma-specific epigenetic changes, mRNA and protein level aberrations, and changes to microRNA (miRNA) will not be described extensively in this paper. Other publications on these topics exist and offer more thorough descriptions of the epigenetic [
Osteosarcoma is characterised by a high level of genomic instability, in particular one subcategory of instability known as chromosomal instability (CIN) [
CIN is categorised in two subtypes, numerical CIN (N-CIN) and structural CIN (S-CIN). Processes underlying N-CIN are those leading to copy number alterations. N-CIN is manifested in polyploidy, caused by errors in mitosis, aneuploidy, segmental amplifications, or deletions, and unbalanced translocations. S-CIN can result from ineffective DNA damage response mechanisms following exogenous insults or replication errors, leading to aberrant genomic rearrangements, chromosomal breakages, and usually, but not necessarily, gene copy number alterations [
Mutations or deregulation of genes important for mitotic checkpoints is thought to be the underlying cause of CIN [
Telomere maintenance, or lack thereof, is another potential source of the instability typical of osteosarcoma, in addition to reducing the likelihood of favourable outcome in patients with the disease. Telomerase activation is a mechanism by which human cells can bypass their theoretical life span defined by the number of cell divisions required to critically deplete telomere length (the Hayflick limit), thereby avoiding senescence [
The vast majority of studies have been descriptions of osteosarcomas focused on the conventional, high-grade subtypes including the chondroblastic, fibroblastic, and osteoblastic variants. These are the most frequently occurring types of osteosarcoma. The rarer subtypes include telangiectatic, small cell, periosteal, high-grade surface, and low-grade osteosarcoma. These forms often present with distinguishing genetic features infrequent in conventional tumours.
Complex and largely inconsistent genetic alterations are typical of conventional osteosarcoma. Overall, some frequent genetic alterations in conventional osteosarcoma are losses of portions of chromosomes 3q, 6q, 9, 10, 13, 17p, and 18q and gains of portions of chromosomes 1p, 1q, 6p, 8q, and 17p (Table
Frequent genetic alterations in sporadic conventional osteosarcoma.
Genomic region | Event | Frequency | Effected genes | References | |
Tumour suppressor gene(s) | Oncogene(s) | ||||
1q10-q12, 1q21-q31 | Amp | 6–59% | [ | ||
3q13.31 | Del, | 6–80% | [ | ||
5q21 | LOH | 62% | [ | ||
6p12-p21 | Gain, | 16–75% | [ | ||
6p22.3 | Gain, | 60% | [ | ||
7p21 | Del | 36% | [ | ||
8q24.21 | Amp | 7–67% | [ | ||
8q24.4 | Mut | <5% | [ | ||
Gain | 33% | [ | |||
9p21 | Del | 5–21% | [ | ||
10q26 | LOH | 60% | [ | ||
12q13 | Amp | 41% | [ | ||
12q14 | Amp | 10% | [ | ||
12q15 | Amp | 3–25% | [ | ||
13q14.2 | LOH | 19–67% | [ | ||
Mut | 25–35% | [ | |||
16q23.1-q23.2 | Del | 30% | [ | ||
17p11.2-p12 | Amp | 20–78% | [ | ||
17p13.1 | Del, | 29–42% | [ | ||
Mut | 10–39% | [ | |||
18q (MCR 18q21-q23) | Del | 31–64% | [ |
MCR, minimal common region; Del, deletion; Amp, amplification; Mut, mutation.
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
Inactivation of
Loss of cellular control of other components of the pRB pathway is often deduced upon observing genetic alterations in osteosarcoma tumours. As such, pRB-independent mechanisms of pRB pathway deregulation may be present in addition to pRB inactivation. Amplification of the cyclin-dependent kinase gene
Deregulation of
Direct inactivation of
Instability of chromosome 8q has been described by many laboratories, with
Aberrations of the
Amplifications within the short arm of chromosome 6, with a minimal common region at 6p12-p21, have been frequently observed at rates of 16–75% in conventional osteosarcoma tumour specimens [
A number of genes with oncogenic potential lie within chromosome 6p12-p21 and in close proximity to this region.
Other genomic regions frequently altered in copy number but whose potential gene targets are less well characterised in osteosarcoma have been abundantly described. Amplifications of chromosome 1q, at minimal regions including 1q10-q12 and 1q21-q31, occur in 6–59% of tumours in addition to other rearrangements of 1q [
Loss of chromosome 3q, with a minimal common region at 3q13.31, has been observed in 6–80% of tumours [
LOH at chromosome 10q26 has been reported in 60% of a cohort, and the genes
As at chromosome 3q, LOH at chromosome 18q has been frequently observed, but no studies have defined a distinct tumour suppressor gene important in osteosarcoma. Chromosome 18q is lost in 31–64% of specimens [
Telangiectatic osteosarcoma is a rare subtype of the disease, accounting for between 2 and 12% of cases [
Histologically, small cell osteosarcoma can be mistaken for Ewing’s sarcoma, but cytogenetically they lack any consistent genetic alteration. The
The genetic alterations observed in this subtype have been largely inconsistent. Cells in one case were found only with an additional copy of chromosome 17 [
Amplification of the
In one CGH study of low-grade central osteosarcoma, six of seven specimens possessed a single copy number change and there were recurrent gains at 12q13-q14, 12p, and 6p21.1-p21.3 among the cases [
Parosteal osteosarcoma is characterised by a high rate of
Osteosarcoma is characterised by extensive and heterogeneous genetic complexity, which is reflected in the similarly complex epigenetic and expression alterations in tumours [
Chromosome 6p rearrangement. Chromosome 6p12-p21, which contains
The authors are supported by the Canadian Cancer Society through Grant CCRI-020247.