Cytogenetic and molecular techniques so far of limited use in the diagnosis of osteosarcoma; these studies hampered by
- Rarity of these tumors
- Utilization of pre-operative chemotherapy
- Necessary to decalcify specimens prior to tissue processing.
DNA analysis suggests high grade tumors display a hyperdiploid pattern while low grade tumors are more likely to be diploid.
Cytogenetic analysis has shown a variety of complex karyotypic arrangements.
- Most frequent chromosomal band re-arrangements include 1p11-13, 1q10-10 and 1q21-22.
- Whole chromosomal losses more frequent than gains with the most frequent numerical abnormalities including –9, -10, -13 and +1.
Non-germ line mutations of p53 and Rb occur in osteosarcoma
Association between retinoblastoma [RB] and osteosarcoma has long been recognized.
- Children with hereditary RB display an osteosarcoma incidence of up to 1000 times that of the general population.
- RB gene functions as a tumor suppressor gene.
- Penetrance of familial RB is 90-59% but as only 12% of these patients develop osteosarcoma this suggests that additional events are involved in the development of this bone tumor.
- Reports have proposed a role for p19 protein, increased expression of CD4, and alterations of p53 gene.
Retinoblastoma recessive oncogene (Rb) on chromosome 13, band q14, is associated with osteogenic sarcoma (with no prior history of retinoblastoma).
Osteogenic sarcoma is associated with Rb gene
- Rb gene deletions and rearrangements
- Altered expression of Rb transcripts
- Altered Rb protein
Recessive oncogene on chromosome 17p13.1 is involved in development of osteosarcoma.
Inactivation of p53 gene product with loss of growth regulator leads to proliferation and osteogenic sarcoma.
Other molecular markers
- Amplification of murine double minute two [MDM2] has been reported to be more frequent in metastatic or recurrent tumors.
- ErbB-2 expression has also been suggested as a useful marker for metastatic potential.
- Amplification of ‘sarcoma amplified sequence’ [SAS] has been reported in between 36-100% of ‘surface’ osteosarcomas, suggesting an alternative pathway for tumorigenesis for ‘surface’ tumors.
Studies have suggested
Higher levels of TGF beta-1 in high grade versus low grade osteosarcomas suggesting a role for this growth factor in tumor progression.
Expression of TGF beta 3 is correlated with disease progression.
A role for increased dihydrofolate reductase as a marker for Methotrexate resistance.
P-glycoprotein expression as a marker for relapse.
Expression of ‘heat shock protein [hsp] 72 as a marker of a better response to induction chemotherapy.
Read about the cytogenetic changes associated with osteogenic sarcoma in more detail at the Atlas of Genetics and Cytogenetics in Oncology and Haematology