Genetic polymorphisms of smoking-related carcinogen detoxifying enzymes and head and neck cancer susceptibility.

Smoking and the consumption of alcohol are the main risk factors for head and neck cancer. However, interindividual variation in the activity of enzymes involved in the detoxification of tobacco smoke (pro)carcinogens, such as microsomal epoxide hydrolase (mEH), glutathione-S-transferases (GSTs) and uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGTs), may influence the process of carcinogenesis. Genetic polymorphisms of these enzymes may alter their activity and may thus modulate the risk for squamous cell carcinomas of the head and neck (SCCHN). A literature review on the role of mEH, GSTs and UGTs polymorphisms in relation to SCCHN was performed and the results summarized. For mEH polymorphisms, some of the studies revealed a relationship between genetic polymorphisms of these enzymes and an altered risk for SCCHN, whereas others did not. The presence of null polymorphisms in GSTM1 or GSTT1 were associated with an increased risk for SCCHN. For the UGTs, only variants in UGT1A7 and UGT1A10 have been studied, both of which were associated with an altered risk for SCCHN.

COX-2 polymorphisms and the risk for head and neck cancer in white patients.

BACKGROUND: Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether functional genetic polymorphisms in COX-2 may have a risk-modifying effect on head and neck carcinogenesis. METHODS: Blood from 431 white patients with oral, pharyngeal, or laryngeal carcinoma and 438 white healthy controls was investigated for the presence of 2 functional promoter region polymorphisms (-1195A-->G and -765G-->C) in COX-2. RESULTS: Logistic regression analysis did not show differences in COX-2 genotype distributions between patients and controls. Also no differences were found when stratified according to tumor localization, sex, or tobacco consumption. CONCLUSION: In contrast to earlier reports on the role of these COX-2 polymorphisms in mediating susceptibility to squamous esophageal carcinoma in a Chinese population, we could not demonstrate a risk-modifying effect in head and neck carcinogenesis in whites.

Microsomal epoxide hydrolase genotypes and the risk for head and neck cancer.

BACKGROUND: Microsomal epoxide hydrolase (mEH) is an enzyme involved in the metabolism of (pre)carcinogens in tobacco smoke. We investigated whether functional genetic polymorphisms in mEH may have a risk-modifying effect on head and neck carcinogenesis. METHODS: Blood from 429 patients with oral, pharyngeal, and laryngeal carcinoma and 419 healthy subjects was investigated for mEH polymorphisms. RESULTS: Logistic regression analysis did not show differences in mEH genotype distributions between patients and controls, when categorized according to predicted mEH enzyme activity. Also no differences were found when evaluated according to tumor localization, sex, or tobacco consumption. A significantly higher incidence of the 139Arg/Arg variant was found in patients with hypopharyngeal carcinoma compared with controls (OR = 4.39, 95% CI = 1.45 to 13.35). CONCLUSION: In contrast to earlier reports, we could not demonstrate a risk-modifying effect of genetic polymorphisms in mEH on head and neck carcinogenesis, except for the predicted high activity variant in patients with hypopharyngeal carcinoma.

Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer.

Sequence variation in the GSTM1, GSTT1, GSTP1, and CYP1A1 genes may potentially alter susceptibility to head and neck cancers, although evidence from previous studies has not been consistent. To explore these associations, we conducted a meta-analysis of 31 published case-control studies (4635 cases and 5770 controls) and a pooled analysis of original data from nine published and two unpublished case-control studies (2334 cases and 2766 controls). In the meta-analysis, the summary odds ratios (ORs) for head and neck cancer were 1.23 [95% confidence interval (95% CI), 1.06-1.42] for the GSTM1 null genotype, 1.17 (95% CI, 0.98-1.40) for the GSTT1 null genotype, 1.10 (95% CI, 0.92-1.31) for carrying the GSTP1 Val105 allele, and 1.35 (95% CI, 0.95-1.82) for carrying the CYP1A1 Val462 allele. The pooled analysis ORs were 1.32 (95% CI, 1.07-1.62) for the GSTM1 null genotype, 1.25 (95% CI, 1.00-1.57) for the GSTT1 null genotype, 1.15 (95% CI, 0.86-1.53) for carrying the GSTP1 Val105 allele, and 0.98 (95% CI, 0.75-1.29) for carrying the CYP1A1 Val462 allele. Increasing risk of head and neck cancer was observed with inheritance of increasing numbers of modest risk genotypes at the three GST loci (P for trend = 0.04), with the combination of carrying the GSTM1 null, GSTT1 null, and GSTP1 Val105 alleles conferring an OR of 2.06 (95% CI, 1.11-3.81). In conclusion, both the meta- and pooled analysis support modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk, and our pooled analysis supports the notion of greater risk when genotypes at multiple GST loci are considered in a multigenic model.

Polymorphisms of the glutathione S-transferase P1 gene and head and neck cancer susceptibility.

BACKGROUND: Factors determining the individual susceptibility to head and neck squamous cell carcinoma (HNSCC) are still largely unknown. An imbalance between enzymes involved in the toxification and detoxification of (pre)-carcinogens closely related to HNSCC, which may appear during smoking and alcohol consumption, may play a role. Genetic polymorphisms in glutathione S-transferases (GSTs) often result in altered detoxification, which may contribute to individual susceptibility to HNSCC. METHODS: We studied the frequencies of polymorphic variants in the GSTP1 gene in 235 patients with HNSCC and 285 healthy controls. In addition, data on exposure to alcohol and tobacco consumption were recorded. DNA was extracted from whole blood, and polymerase chain reaction-based methods were used to detect genetic polymorphisms. RESULTS: In patients with HNSCC and control groups, the homozygous GSTP1 BB genotype was observed in 12.3% and 13.6%, respectively. No statistical differences were found for the GSTP1 AA and GSTP1 AB/GSTP1BB genotypes. CONCLUSIONS: Our study showed that genetic polymorphisms of GSTP1 are not associated with altered susceptibility to HNSCC.

The association between glutathione S-transferase P1 genotype and plasma level in head and neck cancer.

OBJECTIVES/HYPOTHESIS: Glutathione S-transferase P1-1 (GSTP1-1) is an important enzyme because it plays a major role in many detoxification reactions, including tobacco-related metabolic products. GSTP1-1 is the most abundant of all glutathione S-transferase (GST) enzymes in normal human head and neck epithelium, whereas it is overexpressed in head and neck malignancies. At least three different GSTP1 genotypes exist, AA, AB, and BB, which have been correlated with reduced enzyme activity. Many authors have studied the GSTP1 genotypes in relation to the risk for human head and neck squamous cell carcinoma (HNSCC). A correlation between GSTP1-1 genotype and GSTP1-1 plasma levels has not been made before. We investigated the correlation between GSTP1 genotype and GSTP1-1 plasma levels. STUDY DESIGN: To evaluate the possible association between the genetic polymorphisms in GSTP1 and the phenotypic expression (GSTP1-1 plasma levels) in patients with HNSCC. METHODS: GSTP1 genotype and GSTP1-1 plasma level were established in 87 patients with HNSCC and 51 patients with benign head and neck lesions who served as control subjects. RESULTS: For all GSTP1 genotypes (AA, AB, and BB) in patients with HNSCC, the mean plasma GSTP1-1 values were significantly higher compared with the control subjects. There was no significant difference in the plasma GSTP1-1 levels between the different genotypes in patients with HNSCC. CONCLUSION: There is no association between GSTP1 genotype and GSTP1-1 plasma levels in patients with head and neck cancer.