Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

Abstract

BackgroundNon-melanoma skin cancers are one of the most common human malignancies accounting for 2–3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.MethodsWe studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).ResultsWe found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.ConclusionsThese studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.

Protein Oxidative Damage in UV-Related Skin Cancer and Dysplastic Lesions Contributes to Neoplastic Promotion and Progression

“…A dimorphism of the TP53 gene at codon 72 has been described generating two biologically distinguishable variants, the P72 and the R72 variant, both critical to the cellular response to UV damage response. Addressing the still unresolved question of their respective implications in skin carcinogenesis is out of the scope of this communication, nonetheless it is interesting to note that the almost even prevalence of the Arg/Arg and Pro/Arg genotypes and the absence of the Pro/Pro genotype in our cases agrees with the data already reported for European populations [31] suggesting that, as far as the codon 72 is concerned, our series of patients do not represent a peculiar subset of population. Regarding the UV signature at specific hotspots in exon 7, the ARMS-PCR did not yield conclusive results while direct sequencing revealed a high number of point mutation, none of which however consisted in the canonical TT>CC or CT > CC transversion [1], suggesting that perhaps this kind of mutations, although specific, are comparatively infrequent in late lesions.…”

HPV Has Left the Building—the Absence of Detectable HPV DNA and the Presence of R Allele/S for the P72R Polymorphism in theTP53Gene May Call for More Aggressive Therapeutic Approach in HPV-Associated Tumours

“…Apparently, the expectations that lower capacity for DnA repair was always detrimental in terms of outcome were not met. What is more, it has been repeatedly demonstrated that the carriers of the R variant of the P72R polymorphism and especially the RR homozygotes were overrepresented (not underrepresented, as could be expected) in study groups with hPV-associated tumours (cervical carcinoma, Scchn) compared with the normal population, regardless of the smoking status (the latter being regarded as a major environmental risk factor for HPV-related carcinogenesis) (7,18,21). The finding of higher percentage of RR homozygotes, however, was found to be correct for true carcinoma only and not for precancerous highgrade cin (37).…”

Analysis of p53 codon 72 polymorphism and HPV 5,8 E6 oncoprotein expression in Basal cell carcinoma in Basrah

“…The low frequency p53 Arginine allele in the present study (10.3% for cases and 6.5% for controls) could be explained by the fact that frequency of p53 codon 72 Arginine allele increases with geographic distance from the equator and that fair skin population have higher frequency of p53 Arg allele than dark skin population. [21,22] Most of these studies were conducted on Caucasian population and only one involves Asian population in Iran 8 which included the BCC and revealed no significant difference in the p53 genotypes between patients and controls but indicated an increase in the frequency of arginine allele among sun exposed compared to control which may affect the risk of UV induced BCC. However, a positive association of the p53 codon 72 and BCC was found in transplant patient by McGregor, et al [1] but not in immunocompetent group.…”