Osteosarcoma is a primary bone malignancy that typically occurs during adolescence but also has a second incidence peak in the elderly. It occurs most commonly in the long bones, although there is variability in location between age groups. The etiology of osteosarcoma is not well understood; it occurs at increased rates in individuals with Paget disease of bone, after therapeutic radiation, and in certain cancer predisposition syndromes. It also occurs more commonly in taller individuals, but a strong environmental component to osteosarcoma risk has not been identified. Several studies suggest that osteosarcoma may be associated with single nucleotide polymorphisms in genes important in growth and tumor suppression but the studies are limited by sample size. Herein, we review the epidemiology of osteosarcoma as well as its known and suspected risk factors in an effort to gain insight into its etiology.
Osteosarcoma, the most common primary bone malignancy, typically during the adolescent growth spurt but there is a second, smaller peak in the elderly [
Osteosarcoma represents approximately 55% of child and adolescent malignant bone tumors in the US [
In the US, using population data from the Surveillance, Epidemiology, and End Results (SEER) program, osteosarcoma incidence has been shown to vary by race based on the age of onset [
It has been reported that, when a wide range of ages are combined, males are affected with osteosarcoma more frequently than females [
Osteosarcoma occurs most frequently in the lower long bones [
The anatomic site distributions do not vary significantly by sex or race in young patients [
Survival rates vary by age, gender, disease stage, and anatomic site (Figure
Females have higher survival rates than males [
Older patients may have unique tumor biology, for example, more axial tumors or other factors associated with a poorer prognosis, such as Paget disease (see below) and response to therapy due to age-related adjustments in therapeutic regimens, which could contribute to their worse overall survival [
Studies of environmental exposures and rare cancers, such as osteosarcoma, are challenging and often limited by sample sizes. Most studies are case-control, ecologic, and/or descriptive in nature. This is because the extremely large cohorts required to study these cancers are nearly impossible to conduct. For example, even in a cohort of one million individuals, only 4 or 5 would be expected to develop osteosarcoma. Studies of environmental exposures and osteosarcoma are often combined with studies of other bone tumors, including Ewing sarcoma and others. This makes separating the potentially etiologic clues even more challenging. The reader is referred to a recent, comprehensive review of these studies [
Many years ago, it was hypothesized that fluoride could contribute to osteosarcoma risk. This was based, in part, on the fact that it is taken up by and stored in bones and on
Therapeutic radiation is a proven risk factor for osteosarcoma. It was noted to occur more frequently than expected in survivors of Hodgkin disease who received therapeutic radiation [
Since osteosarcoma occurs most commonly during puberty, a time of rapid bone growth and remodeling, it is highly plausible that factors related to growth and development play a role in osteosarcoma etiology. Case reports of osteosarcoma occurring in individuals with acromegaly, a growth disorder caused by over production of growth hormone, lent further support to this hypothesis [
Osteosarcoma incidence is highest during puberty when endogenous sex hormones, growth hormones, and insulin-like growth factor 1(IGF1) levels are at their highest, so this biological pathway is likely to play an important role in osteosarcoma etiology. Insulin-like growth factors (IGFs) play critical roles in carcinogenesis and circulating levels are associated with risk of several cancers [
The association between taller stature and increased risk of developing osteosarcoma was first reported in 1967 [
A recent meta-analysis of height and osteosarcoma compiled individual osteosarcoma patient data on 1067 osteosarcoma cases derived from 5 published [
The meta-analysis (Mirabello et al., Under Review), and a separate study of 962 patients with osteosarcoma [
Numerous epidemiologic studies have evaluated associations between high birth weight and cancer. This is based on the hypothesis that high birth weight may be the result of multiple factors that are also associated with cancer. For example, IGFs are important in fetal development [
Review of the literature identified five published studies that evaluated the potential association between birth weight and osteosarcoma; four were null [
Paget disease of bone is a relatively common metabolic bone disorder that typically occurs in older individuals [
The co-occurrence of osteosarcoma in the setting of abnormal bone remodeling due to Paget disease of the bone suggests that osteosarcoma may be etiologically related to abnormal bone remodeling [
Chromosomal aneuploidy is common in osteosarcoma cells which suggests that somatic or germline chromosomal instability could potentially predispose an individual to osteosarcoma [
Inherited disorders associated with increased rates of osteosarcoma.
Disorder | Gene | Chromosome | Autosomal inheritance pattern |
---|---|---|---|
Li-Fraumeni Syndrome | 17p13.1 | Dominant | |
Retinoblastoma | 13q14.2 | Dominant | |
Rothmund Thomson Syndrome | 8q24.3 | Recessive | |
Werner Syndrome | 8p12 | Recessive | |
Bloom Syndrome | 15q26.1 | Recessive | |
Diamond Blackfan Anemia | Ribosomal protein genes, including | multiple | Dominant |
Association studies of single nucleotide polymorphisms and osteosarcoma risk. Abbreviations: SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval.
First Author, Year, Reference | No. cases/no. controls | Study Design | Gene | Main Finding(s) |
---|---|---|---|---|
Patiño-Garcia, 2000, [ | 63/111 | Case-Control | Tumor Necrosis Factor- | Evaluated 3 SNPs in the promoter. |
Ruza, 2003, [ | 72/143 | Case-Control | Vitamin D Receptor ( | 3 SNPs (FokI, ApaI, TaqI) studied. FokI |
Estrogen Receptor ( | 2 variants (Pvu II and XbaI) evaluated were not associated with osteosarcoma | |||
Collagen 1 | 1 variant studied (Msc 1) was not associated with osteosarcoma. | |||
Savage, 2007, [ | 104/74 | Hospital-based Case-Control | Tumor Protein p53 ( | 12 tag-SNPs in |
Savage, 2007, [ | 104/74 | Hospital-based Case-Control | Insulin-like Growth Factor 2 Receptor ( | Evaluated 52 SNPs in 13 growth-related genes. Two linked |
Koshkina, 2007, [ | 123/510 | Case-Control | Fas (TNF receptor superfamily, member 6; | 4 SNPs in |
Toffoli, 2009, [ | 201/250 | Case-Control | Mdm2 p53 binding protein homolog ( | 1 SNP in |
Tumor Protein p53 ( | 1 SNP evaluated, rs1042522 (Ex4+119C>G, P72R), was associated with survival. | |||
Hu, 2010, [ | 168/168 | Case-Control | Transforming growth factor beta receptor 1 ( | 1 variant evaluated (TGFBR1*6A) was associated with increased susceptibility (OR 4.6, 95% CI 2.3–7.9, |
Mirabello, 2010, [ | 99/1430 | Hospital-based Case-Control | 8q24 region | Evaluated 214 SNPs, including 9 previously associated with cancer. Strongest association noted at rs896324 in additive model (OR 1.75, 95% CI 1.13–2.69, |
Inherited cancer predisposition syndromes are a heterogeneous group of disorders. There are several disorders in which higher rates of osteosarcoma are noted (Table
The careful characterization of families with high rates of breast cancer, sarcomas, and other cancers by Li and Fraumeni Jr. in 1969 led to the recognition of the syndrome now known as Li-Fraumeni syndrome (LFS) [
Retinoblastoma is a malignant retinal tumor that typically occurs prior to the age of 5. It is caused by mutations in the
Increased rates of osteosarcoma are also present in individuals with germline mutations in DNA helicase genes, including Rothmund Thomas syndrome (RTS), Werner syndrome, and Bloom syndrome. RTS is a rare, autosomal recessive disorder caused by mutations in the DNA helicase
Bloom syndrome, caused by autosomal recessive inheritance of mutations in the
Werner syndrome is a premature aging syndrome which typically presents after the first decade of life [
Diamond Blackfan anemia (DBA) is another inherited disorder associated with increased risk of osteosarcoma [
The inherited disorders caused by rare, highly-penetrant mutations and associated with osteosarcoma described above explain only a very small percentage of all osteosarcoma cases. It occurs more often in individuals without a family history of cancer or other medical problems. Several studies have been conducted in an effort to understand the contribution of common genetic variants, such as SNPs, to osteosarcoma risk (Table
Most of the studies of SNPs and osteosarcoma conducted to date have been limited by sample size and therefore should be considered exploratory in nature (Table
In a second study, the same group hypothesized that variants in the estrogen receptor (
Since mutations in
In a different study of the p53 pathway, Toffoli et al. genotyped the Pro72Arg (rs1042522, Ex4+119C>G) SNP in
The first study to evaluate SNPs in growth-related genes did so based on the hypothesis that since osteosarcoma most commonly occurs during a period of active growth, that variants in genes that regulate pubertal growth could be important osteosarcoma risk factors. Common SNPs in 13 growth-related genes were also evaluated as candidate risk modifiers in the BDISO. Of the 52 SNPs evaluated, two correlated SNPs in insulin-like growth factor receptor 2 (
SNPs in the 8q24 chromosomal region are being intensely studied because genome-wide association studies (GWAS) have consistently found them to be associated with risk of adult onset cancers, including prostate, breast, colon, and others [
The Fas protein (gene name
TGF-
As a whole, the studies conducted, to date, of common genetic variants and osteosarcoma risk have yielded promising results. Their strength lies in the fact that they have evaluated genes which have a high biologic likelihood of being related to osteosarcoma etiology based on laboratory and/or other epidemiologic studies. However, the results of all the studies described above and in Table
Some progress has been made in understanding the cause of osteosarcoma, but we still have much to learn. The biggest clue generated in the study of osteosarcoma epidemiology is its association with either rapid or abnormal growth. Its occurrence primarily during the adolescent growth spurt and association with tall height at diagnosis show that bone growth is clearly an important factor. It is not known whether or not tall stature, in and of itself, is the key, or if it is taller stature than expected based on parental heights or due to height velocity during puberty. An ongoing Children’s Oncology Group epidemiology study which will investigate parental height and growth charts of children and adolescents with osteosarcoma will help shed light on this question. Future clinical and laboratory studies should also carefully evaluate the complex hormonal changes that occur before, during, and after puberty.
The association of osteosarcoma with the abnormal bone remodeling present in Paget disease also warrants more careful examination. The role of variants in genes of the RANKL-NF-
The studies of rare, but highly penetrant, cancer predisposition syndromes can shed some light on the biological mechanisms of osteosarcoma. In general, the cancers that occur in individuals with the cancer predisposition syndromes described above occur at much younger ages than in the same cancer types in the general population. The fact that several of these syndromes include osteosarcoma in the phenotype suggests that there may be common genetic mechanisms which also contribute to the apparently sporadic occurrence of osteosarcoma. It is also likely that the genetic contribution to cancers which occur in the first two decades of life, such as osteosarcoma, is greater than in cancers which do not occur until many decades later. In childhood cancer, there has been considerably less time for exposure to known and unknown environmental carcinogens.
The contribution of environmental exposures to osteosarcoma and to other cancers of children and young adults is not known. The heterogeneity and relative rarity of these cancers create significant complexity in study design and interpretation. In addition, it is likely that a combination of environmental exposure and genetic risk factors contribute to cancer risk. Large, longitudinal, cohort studies of the cancers of children and young adults are required to address these study design issues and likely contribution of multiple factors. The International Childhood Cancer Cohort Consortium (I4C) is a multi-institutional, international collaborative group of childhood cohort studies that is working to better understand the etiology of childhood cancer [
Like many cancers, the etiology of most osteosarcoma remains unknown. Epidemiology studies have provided many important clues, such as associations with puberty, height, and disorders of bone growth and remodeling. The genetic clues derived from the occurrence of osteosarcoma in the setting of germline mutations in genes such as