MUTATIONS IN THE TP53 GENE AND PROTEIN EXPRESSION OF P53, MDM-2 AND P21 WAF-1 IN PRIMARY CERVICAL CARCINOMAS WITH NO OR LOW HUMAN-PAPILLOMAVIRUS LOAD/

Several studies have focused on the role of p53 inactivation in cervic al cancer, either by inactivating mutations in the TP53 gene or by deg radation of the p53 protein by human papillomavirus (HPV). In this stu dy, primary cervical carcinomas from 365 patients were analysed for pr esence of HPV using both consensus primer-sets and type-specific prime r-sets. Nineteen samples were determined to have no or tow virus load, and were selected for further analyses: mutation screening of the TP5 3 gene using constant denaturant gel electrophoresis (CDGE) followed b y sequencing, and protein expression of p53, MDM2 and p21 using immuno histochemistry (IHC). Mutations in the TP53 gene were found in eight s amples (42%). Elevated p53 protein expression was significantly associ ated with presence of a mutation (P < 0.007). P21 protein expression w as detected in 16 of the 19 carcinomas. No p21 expression was seen in normal cervical tissue. Two samples, both with wild-type p53, had elev ated MDM2 expression. Compared with a previous study from our group, o f mainly HPV-positive cervical carcinomas, in which only one sample wa s found to contain a TP53 mutation, a significantly higher mutation fr equency (P < 0.001) was found among the carcinomas with no or low Viru s load. Although p53 inactivation pathways are not detected in every t umour, our study supports the hypothesis that p53 inactivation, either by binding to cellular or viral proteins or by mutation, is essential in the development of cervical carcinomas.