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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.

SUBMITTER: Li C

PROVIDER: S-EPMC2818282 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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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.

Li Chunying C Lu Jiachun J Liu Zhensheng Z Wang Li-E LE Zhao Hui H El-Naggar Adel K AK Sturgis Erich M EM Wei Qingyi Q

Cancer prevention research (Philadelphia, Pa.) 20100119 2

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 ...[more]

PMID: 20086182

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Project description:BackgroundTranscriptional dysregulation is one of the most important features of cancer genesis and progression. Applying gene expression dysregulation information to predict the development of cancers is useful for cancer diagnosis. However, previous studies mainly focused on the relationship between a single gene and cancer. Prognostic prediction using combined gene models remains limited.Materials and methodsGene expression profiles were downloaded from The Cancer Genome Atlas and the data sets were randomly divided into training data sets and test data sets. A six-gene signature associated with head and neck squamous cell carcinoma (HNSCC) and overall survival (OS) was identified according to a training cohort by using weighted gene correlation network analysis and least absolute shrinkage and selection operator Cox regression. The test data set and gene expression omnibus (GEO) data set were used to validate this signature.ResultsWe identified six candidate genes, namely, FOXL2NB, PCOLCE2, SPINK6, ULBP2, KCNJ18, and RFPL1, and, using a six-gene model, predicted the risk of death of head and neck squamous cell carcinoma in The Cancer Genome Atlas. At a selected cutoff, patients were clustered into low- and high-risk groups. The OS curves of the two groups of patients had significant differences, and the time-dependent receiver operating characteristics of OS, disease-specific survival (DSS), and progression-free survival (PFS) were as high as 0.766, 0.731, and 0.623, respectively. Then, the test data set and the GEO data set were used to evaluate our model, and we found that the OS time in the high-risk group was significantly shorter than in the low-risk group in both data sets, and the receiver operating characteristics of test data set were 0.669, 0.675, and 0.614, respectively. Furthermore, univariate and multivariate Cox regression analyses showed that the risk score was independent of clinicopathological features.ConclusionThe six-gene model could predict the OS of HNSCC patients and improve therapeutic decision-making.

Dataset Information

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.

Publications

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.

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