The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck

Abstract

Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.

Figure 1. Graphic presentation of apoptotic index by age and CASP8 genotypes

A, Scatter plot for correlation between apoptotic index (%) and age of 170 cancer-free subjects: the apoptotic index increases as age increases. B, Boxplot for apoptotic index by CASP8 H302D genotypes: there is no trend of decreased apoptotic index as the number of the variant C allele increases. C, Boxplot for apoptotic index by CASP8 -652 6N genotypes: these is an insignificant trend of increased apoptotic index as the number of the D (deletion) allele increased, which is consistent with its observed inverse association, assuming the lymphocytes serve as the surrogates for target cells.