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

Abstract

Several studies have focused on the role of p53 inactivation in cervical cancer, either by inactivating mutations in the TP53 gene or by degradation of the p53 protein by human papillomavirus (HPV). In this study, primary cervical carcinomas from 365 patients were analysed for presence of HPV using both consensus primer-sets and type-specific primer-sets. Nineteen samples were determined to have no or low virus load, and were selected for further analyses: mutation screening of the TP53 gene using constant denaturant gel electrophoresis (CDGE) followed by sequencing, and protein expression of p53, MDM2 and p21 using immunohistochemistry (IHC). Mutations in the TP53 gene were found in eight samples (42%). Elevated p53 protein expression was significantly associated with presence of a mutation (P < 0.007). P21 protein expression was detected in 16 of the 19 carcinomas. No p21 expression was seen in normal cervical tissue. Two samples, both with wild-type p53, had elevated MDM2 expression. Compared with a previous study from our group, of mainly HPV-positive cervical carcinomas, in which only one sample was found to contain a TP53 mutation, a significantly higher mutation frequency (P < 0.001) was found among the carcinomas with no or low virus load. Although p53 inactivation pathways are not detected in every tumour, 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. Images Figure 1

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

“…The p53 Arg72Pro polymorphisms were analysed by procedures modified from those described by Helland et al [35] and Ara et al [36]. A 199-bp sequence containing the polymorphic site was amplified by PCR using the following primers:…”

MDM2 Oncogene as a Novel Target for Human Cancer Therapy

“…Using immunohistochemical techniques, overexpression of MDM2 protein (with or without gene amplification) has been reported in various human cancers, including breast cancer [75,96,[114][115][116][117], ovarian cancer [118,119], cervical carcinoma [120][121], endometrial carcinoma [122], choriocarcinoma [123], soft tissue sarcomas, osteosarcomas, rhabdomyosarcomas, leiomyomas, and leiomyosarcomas [88,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139], head and neck cancers [106,[140][141][142][143][144][145][146][147][148][149][150], lung and bronchogenic carcinomas [103][104][105][151][152]…”

The hypermethylation and protein expression of p16 INK4A and DNA repair gene O 6-methylguanine-DNA methyltransferase in various uterine cervical lesions

“…Cervical cancer development is the result of complex interactions between the host and environmental factors, undergoing stepwise progression from low-grade to high-grade dysplasia to invasive carcinoma. In this pathway, activation or inactivation of various cancer-related genes is involved [3,17,31,39]. Recent studies have demonstrated the promoter hypermethylation of several genes, such as DAPK, p16 INK4A , O6-methylguanine-DNA methyltransferase (MGMT), APC, HIC-1, E-cadherin, RARß, FHIT, GSTP and hMLH1, associated with cervical carcinogenesis [13,24,43,45,48].…”