A novel functional variant (-842G>C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity.
PIN1, a new peptidyl-prolyl cis/trans isomerase, regulates the conformation of Pro-directed phosphorylation sites, revealing a new postphosphorylation regulatory mechanism. PIN1-induced conformational changes potentiate multiple oncogenic signaling pathways, and PIN1 overexpression is reported as a prevalent and specific event in human cancers. In this study, we tested the hypothesis that common polymorphisms in the coding and promoter regions of PIN1 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped three selected PIN1 polymorphisms (-842G>C, -667T>C and Gln33Gln) in a hospital-based case-control study of 1006 patients with SCCHN and 1007 cancer-free control subjects. We found that the -842C variant genotypes were associated with decreased risk for SCCHN [Odds Ratio (OR) = 0.74; 95% confidence interval (CI) = 0.59-0.93 for the CG genotype, OR = 0.82; 95% CI = 0.34-2.01 for the CC genotype and OR = 0.74; 95% CI = 0.59-0.93 for CG+CC genotypes, compared with the GG genotype]. However, no altered risks were observed for -667T>C and Gln33Gln polymorphisms. Further experiments of the reporter gene expression driven by the allelic PIN1 promoter showed that the -842G allele had a higher activity than that driven by the -842C allele, suggesting that the -842C allele was associated with a reduced transcriptional activity, a finding consistent with a reduced risk observed in the case-control analysis. Large prospective studies of diverse ethnic groups and diverse cancer sites are warranted to validate our findings.
Lu, J; Hu, Z; Wei, S; Wang, L-E; Liu, Z; El-Naggar, AK; Sturgis, EM; Wei, Q
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