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.
Highlights
Non-melanoma skin cancer (NMSC) is the most common cancer among Caucasians, outnumbering the total of all other cancers combined [1]
The importance of UV-irradiation in the development of cutaneous squamous cell carcinoma (SCC) is well established, and studies of premalignant actinic keratosis (AK) lesions and experimental skin cancers in mice suggest that a key event in the development of skin SCC is the acquisition by epidermal keratinocytes of UV-induced Tp53 gene mutations, characteristically (C to T or CC to TT) transitions at dipyrimidine sites [6,7,8]
Increased risk for SCC has not been a prominent feature of individuals with Li Fraumeni syndrome, which is characterized by the presence of mutations of both Tp53 alleles [15], suggesting that factors in addition to Tp53 mutations are required for the development of SCC
Summary
Non-melanoma skin cancer (NMSC) is the most common cancer among Caucasians, outnumbering the total of all other cancers combined [1]. The ability of UV-irradiation to induce Tp53 mutations is important as the Tp53 gene plays a critical role in apoptosis, cell proliferation, and DNA repair. Mutations in this gene are among the most common mutations observed in human tumors, including SCC [9]. Non-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. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas
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