Role of a p53 polymorphism in the development of human papilloma-virus-associated cancer

Abstract

The E6 oncoprotein derived from tumour-associated human papillomaviruses (HPVs) binds to and induces the degradation of the cellular tumour-suppressor protein p53. A common polymorphism that occurs in the p53 amino-acid sequence results in the presence of either a proline or an arginine at position 72. The effect of this polymorphism on the susceptibility of p53 to E6-mediated degradation has been investigated and the arginine form of p53 was found to be significantly more susceptible than the proline form. Moreover, allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygous for arginine 72 are about seven times more susceptible to HPV-associated tumorigenesis than heterozygotes. The arginine-encoding allele therefore represents a significant risk factor in the development of HPV-associated cancers.

Reduced rate of human papillomavirus infection and genetic overtransmission of TP53 72C polymorphic variant lower cervical cancer incidence

“…Furthermore, there was a statistically significant dose‐dependent relationship for TP53 G72C genotypes (Cochran‐Armitage trend test, P  = .011), indicating an ordering in the effect of the G allele in HPV‐positive patients. In fact, it is this allele that is deemed more prone to degradation by high‐risk HPV‐E6 oncoprotein 10. Consistent with our results, Hu et al21 also reported that the TP53 G72 (Arg) was significantly overtransmitted in Caucasian CxCa subjects of a family‐based association study where HPV was determined, especially in subjects who were infected with HPV16/18 21.…”

“…Following the first description of the potential usefulness of the Arg genotype as a marker of risk to develop uterine cervix neoplasia,10 there were many studies that examined the association between CxCa and TP53 G72C SNP; however, the results in various populations were inconsistent 21. Nevertheless, there is substantial collective evidence to support a sound association specifically when HPV status is considered.…”

“…Moreover, emerging genome‐wide association studies have supported this assumption and detected susceptibility loci formerly not implicated in CxCa development 9. The pivotal gene encoding the tumor suppressor protein p53 ( TP53 ) is the most widely evoked candidate gene with an alleged ability to affect the oncogenic potential of the viral HPV‐E6 protein 10. The p53 protein is a central regulator of cell cycle and DNA repair that orchestrates several pathways to preserve genomic integrity, which can be deregulated by HPV infection.…”

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…The replacement of proline with arginine abolishes one of the ®ve PXXP motifs. Recently it has been reported that the p53 Arg is signi®cantly more susceptible than p53 Pro to E6-mediated degradation to human papilloma virus (HPV)-induced tumours in homozygous p53 Arg (Storey et al, 1998). This correlates with the clinical ®nding that individuals homozygous for Arginine 72 are more susceptible to human papillomavirus associated tumorigenesis than heterozygotes, at least in certain populations (Storey et al, 1998).…”

“…Although deletion of the proline-rich domain does not a ect transactivation of several promoters, such as WAF1, mdm2 and BAX, it does alter transcriptional repression (Venot et al, 1998). A chief point of interest is the fact that p53 gene is polymorphic at amino acid 72 which results in either a proline (p53 Pro) or a arginine (p53 Arg) at this position (Storey et al, 1998). The replacement of proline with arginine abolishes one of the ®ve PXXP motifs.…”