Relationship Between p53 Codon 72 Polymorphism and Susceptibility to Sunburn and Skin Cancer

Abstract

Upregulation of p53 protein induces either growth arrest or apoptosis in response to cellular injury This is signaled from a highly conserved p53 domain between codons 64 and 92, where a functional polymorphism results in either a proline (p53-72P) or an arginine (p53-72R) at codon 72. Preliminary studies suggest that p53-72R may be a risk factor for cervical cancer and, consistent with this, preferential mutation and retention of the p53-72R allele has also been demonstrated in other cancers of squamous cell origin. Here we examine the relationship between allelic forms of p53 and nonmelanoma skin cancer, by determining the correlation with susceptibility to sunburn, which is a known risk factor, and then by p53 sequence analysis of a large series of tumors. We found a significant positive association between p53-72R and susceptibility to sunburn, as assessed by skin phototype and minimal erythemal dose following solar-simulated radiation (p = 0.0001 for trend). We also found a significant association between p53-72R homozygosity and nonmelanoma skin cancer in renal transplant recipients (basal cell carcinoma, p < 0.01; squamous cell carcinoma, p < 0.05) but not in immunocompetent patients compared with skin type matched controls. p53 sequence data revealed mutations in 30 of 70 (42.9%) nonmelanoma skin cancers, 28 (93%) of which were in the p53-72R allele. Loss of heterozygosity occurred more frequently in p53-72RP than in p53-72RR tumors (p = 0.0001) with preferential loss of p53-72P in heterozygotes (p = 0.016), irrespective of the mutant status of the concomitant allele. Together these data infer functional differences between polymorphic forms of p53 that are likely to be relevant to skin carcinogenesis.

A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis

“…Although inactivating mutations in the tumor suppressor p53 gene are one of the most common genetic changes in human cancers (29 -31), a germ line mutation exists in the p53 gene at codon 72 within the transactivation domain-II that can alter apoptotic rates, cancer incidence, and anti-cancer drug responses (32,33). Interestingly, a relatively rare germ line mutation exists in the p53 gene at a MAPK kinase phosphorylation site near the p53 transactivation domain at Ser-47.…”

p73 can suppress the proliferation of cells that express mutant p53

“…A polymorphism of p53 at codon 72 in exon 4 encoding either proline or arginine has been reported to influence the risk for certain types of cancer, including human papillomavirus (HPV)-associated cervical and nonmelanoma skin cancers (Storey et al, 1998;McGregor et al, 2002;Saranath et al, 2002), and bladder cancer (Soulitzis et al, 2002). This correlation has been proposed to be due to the increased susceptibility of p53 to degradation by HPV E6 when p53 is homozygous for arginine at codon 72 (Storey et al, 1998).…”

Arrayed Primer Extension Resequencing of Mutations in the TP53 Tumor Suppressor Gene: Comparison with Denaturing HPLC and Direct Sequencing

“…2 of the online Data Supplement). This polymorphism may play a role in cancer susceptibility (21,22 ) and response to therapy (2 ). Recently, Bonafe et al (23 ) reported that preferential loss of the codon 72P allele in breast tumors of heterozygous patients was associated with a significant decrease in disease-free and overall survival.…”