1) To analyze the expression of Ki-67, p53 and p16(INK4a) in cervical cancer, 2) to correlate the relative expression of these proteins as well as clinical parameters with the stage of disease, and 3) to determine the HPV DNA prevalence and subtype distribution.
Cervical carcinoma is associated with certain types of human papillomaviruses expressing the E6 and E7 oncogenes, which are involved in carcinogenesis through their interactions with the p53 and pRB pathways, respectively.
Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively.
A common polymorphism of p53, encoding either proline or arginine at position 72, affects the susceptibility of p53 to E6-mediated degradation in vivo; Caucasian women homozygous for arginine 72 reportedly are about seven times more susceptible to HPV-associated carcinoma of the cervix than heterozygotes.
A polymorphism at codon 72 of p53 results in translation to either arginine (p53Arg) or proline (p53Pro), and recent study showed that Caucasian women with arginine form of p53 are more susceptible to HPV-associated carcinoma of the cervix.
A. Storey et al.[Nature (Lond.), 393: 229-234, 1998)] reported a 7-fold increased risk of cervical cancer associated with having an Arg/Arg polymorphism at codon 72 of p53 compared with the Pro/Arg heterozygotes (odds ratio, 7.4; 95% confidence interval, 2.1-29.4).
Accordingly, these data demonstrate that the anticancer activity of B1 is associated with the activation of p53 and the release of cytochrome c, which suggest that B1 might have therapeutic potential against cervix carcinoma as an effective lead compound.
Although a high incidence of HPV DNA integration and a low incidence of p53 mutation were confirmed in cancer of the uterine cervix, there was no inverse association between integration of HPV types 16 and/or 18 DNA and p53 mutation.
Although falling short of statistical significance reduces the strength of the conclusion, data presented here imply that p53 gene mutation, particularly along with intermediate-risk HPV types, may constitute one pathogenetic factor in cervical carcinoma affecting elderly women.
Although genetic variation in TP53 might affect the natural history of HPV and cervical cancer, further work is needed to elucidate the possible mechanism.
Although the p53 arginine allele is itself an important risk factor for cervical cancer, the combined risk with LOH of Rb, which appears to be greater, might indicate a possible epistatic effect of the two genes/polymorphisms.
Among the six hot-spot codons of TP53 gene, three codons (175, 248 and 273) were the most commonly mutated in both types of cervical cancer, one codon (249) mainly in squamous cell carcinoma and one codon (282) only in adenocarcinoma.
An association between codon-72 p53 polymorphism and risk of human papillomavirus (HPV)-induced cervical cancer has been found recently, but it has been difficult to replicate.
As the wt-p53 gene apparently plays a negative role in growth regulation of cervical carcinoma cells, this gene may possibly be of some use for treating subjects with a cervical carcinoma.
Because most HPV-positive cervical carcinoma cell lines contain wild-type p53 whereas HPV-negative cell lines have point mutations in the p53 gene, a major role in the development of HPV-negative cervical cancer has been attributed to p53.
Conflicting results regarding the association of a polymorphism at codon 72 of the p53 tumour suppressor gene and susceptibility to develop human papilloma virus (HPV)-associated cervical cancer have been published over the last year, implicating differences in ethnic background, sample origin, sample size and/or detection assay.
Constant expression of E6 and E7 mRNA by high-risk human papillomaviruses (HPV) abrogates p53 and retinoblastoma protein function, respectively, and is essential for the development of cervical cancer.