Table 1 Additional genes implicated in osteosarcoma (not discussed in text)
From: Genetically engineered mouse models and human osteosarcoma
Gene | Human genetic disorder? | Gene function / Relevance to cancer | OS penetrance? OS relevance? | Mouse model generated? |
|---|---|---|---|---|
p14ARF | No | Encoded by the CDKN2a locus; Binds to MDM2-p53 complex to prevent p53 degradation [106] | Ectopic expression in OS cells increases chemo-apoptotic sensitivity [107]; Alterations of p14 genes detected in OS tumour samples [108], which its expression is inverse of p53 [109]; methylation of p14 is linked to poor survival rates for OS patients [110]. | Mouse null for the CDKN2a and CDKN2b developed soft-tissue sarcomas [111] |
p16INK4a | No | Encoded by the CDKN2a locus; CDK4 inhibitor; Member of the RB pathway | Loss of p16 expression in OS tumours with gene deletion detected [44, 108, 112, 113]. Loss of expression in pediatric OS is linked to poor survival [114]; Coexpression with Rb is linked to OS tumour relapse [109]. | Mesenchymal stem cells from p16 null mice with overexpressed cMYC developed OS tumours [115]; p16 null mice are larger than wildtype counterparts, and developed soft-tissue sarcomas among other tumour types [116] |
p21CIP1/ CDKN1a | No | Member of p53 pathway; Cell cycle regulator at G1 phase; Contributes to DNA replication & repair | Overexpression resulted ion growth arrest in OS cell lines [117]; p21 expression detected in OS patient samples [118, 119]; interacts with Runx2 to interrupt osteoblast differentiation in OS [120] | Normal development with no tumours detected at 7 months [121]; Spontaneous tumours detected at 16 months, predominantly soft-tissue sarcomas [122]; Soft tissue sarcoma detected in mice with deletions in WRN and p21 [88] |
c-fos | No | Oncogene; transcription factor | Detection of c-fos in spontaneous & radiation-induced OS samples in mice [123]; Overexpression in human OS tumours, especially in relapsed and metastasised tumours [124, 125] | |
Twist | Saethre-Chotzen Syndrome | Transcription factor, downstream of Runx2; transient loss in Twist is required in osteoblast differentiation [128]; Found to inhibit p53-modulated apoptosis through the interaction of ARF [129] | Found to be expressed in soft tissue sarcomas [129]; Twist found to be deleted or amplified in OS tumours [130, 131] | Mice lacking the expression of Twist and APC gave rise to OS tumours [132] |
Wnt signaling-pathway | Regulator of cell proliferation and differentation during embryonic development | Members of the Wnt pathway were detected in OS cell lines with suggested links to metastasis [135, 136] | Inhibition of Wnt signaling (thru the use of DKK) in MSCs resulted in sarcoma formation [137] | |
WWOX | Eosphgeal Squamous Cell Carcinoma [138] | Oxidoreductase, located within fragile site locus [139]; potential tumour suppressor gene [140] | Absent or reduced WWOX expression detected in human OS samples [141] | OS was detected in juvenile wwox null mice [142] |