[TP53 gene aberrations in chondromatous neoplasms: correlation with immunohistochemical p53 accumulation and MDM2...

Histological differentiation between chondroma and chondrosarcoma is a common problem in surgical pathology. In a former study (3) we were able to show, that immuno-histochemical p53-accumulation in chondromatous neoplasias might be an additional hint for malignancy. Now we tried to find out, whether p53-accumulation is caused by TP53-aberrations or functional inactivation of p53-wildtype protein by MDM2. For this purpose, paraffin-embedded material of 80 chondromatous neoplasms (18 chondromas, 18 chondromatous neoplasms of uncertain dignity (i.e. cytologically suspicious but without definite invasive growth), and 44 chondrosarcomas (24 GI, 13 GII, 7 GIII)) were screened for TP53 gene-aberrations by means of DGGE (denaturing gradient gel electrophoresis; exons 5-8). The results were correlated with immunohistochemical p53-accumulation (DO-7, DAKO) and MDM2-expression (AB-1, Oncogene). A total of 43% of all chondromatous neoplasms showed TP53-aberrations in DGGE-analysis, i.e. 27% of chondromas, 50% of chondromatous neoplasms of uncertain dignity, 46% of GI-, 46% of GII- and 71% of GIII-chondrosarcomas. Exon 6 (58% of all cases with aberrations) and exon 8 (47%) were affected most frequently. No significant correlation between TP53-aberration and either p53-accumulation or MDM2-expression was present. A statistically significant correlation could be found between p53-accumulation and MDM2-expression (p < 0.0001). Regarding histological tumor-classification, p53-accumulation and MDM2-expression discriminated between chondromas/chondromatous neoplasms of uncertain dignity and well differentiated chondrosarcomas in a statistically significant manner. In the subgroup of p53-positive and MDM2-negative cases significantly more TP53-aberrations were detected by DGGE-analysis than in the other groups. Interestingly, the subgroup of p53- and MDM2-negative cases showed the second highest rate of TP53-DGGE-aberrations. Nearly 50% of these aberrations, however, were localized in exon 8, a mutation that is known to cause no p53-protein-accumulation. In conclusion, TP53-aberrations occur frequently in chondromatous neoplasms and show no significant association to either immunohistochemical p53-accumulation or MDM2-expression. Functional inactivation of p53 wildtype protein by MDM2-expression seems to be the major cause of p53-accumulation in chondromatous neoplasms and emphasizes the role of these parameters as additional hint for malignancy.