Included are seven cell lines with wild-type p53 (four mesothelioma, one breast cancer, one chondrosarcoma, and one leiomyosarcoma), two liposarcoma cell lines harboring MDM2 amplification and wild-type p53, and one mesothelioma cell line harboring a p53 point mutation.
We identified patient-specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma).
The molecular marker of well-differentiated/de-differentiated liposarcomas is MDM2 gene amplification coupled with protein overexpression and wild-type TP53.
FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs.
These aberrant forms, which are responsible for the accumulation and inactivation of p53, can contribute, together with the p53 independent transforming forms, to liposarcoma transforming pathway.
Lipoma was characterized by a lack of p53 mutation, p53 LOH and p53 protein expression, as well as by mdm2 amplification and mdm2 protein expression. p53 mutation and p53 LOH were found neither in the well-differentiated nor in the dedifferentiated parts of the liposarcoma.
According to our results, p53 protein nuclear expression was detected in 20% (8/40) of the tumours (1 fibrosarcoma, 2 liposarcomas, 1 leiomyosarcoma, 1 rhabdomyosarcoma, 2 Ewing's sarcomas and 1 unclassified sarcoma).
The findings in this study agree with the molecular data and they show the physical association of mdm2 and p53 in fresh liposarcoma surgical specimens.
TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group.
To investigate further a possible role of the two genes in sarcomas, 24 large and deep-seated lipomas and 74 liposarcomas of various subtypes were analysed for mdm2 and p53 overexpression by immunocytochemistry.
The frequency of p53 alterations varied among the different subtypes of bone and soft tissue sarcomas, being observed predominantly in osteosarcomas (8/34 cases), rhabdomyosarcomas (2/3 cases), Ewing's sarcomas (1/5 cases), and liposarcomas (3/21 cases).
In mesenchymal tumours of other lineages, bcl-2 positivity was only found in four out of 12 malignant fibrous histiocytomas and in one out of three liposarcomas. p53 positivity was found in 14 tumours, 13 of which were sarcomas.
We demonstrated a germline p53 replication error in two generations of a Li-Fraumeni family affected with liposarcoma, adrenocortical carcinoma, and osteosarcoma.