A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35)

Polymorphism at CYP and GST gene loci and susceptibility to tobacco related cancers

Exposure to synthetic or natural chemical compounds present in the environment is causally associated with a large proportion of human cancers. Xenobiotic metabolizing enzymes (XMEs) are responsible for the metabolism of many of these exogenous chemicals that are toxic, mutagenic and/ or carcinogenic. The XMEs comprise of phase I enzymes that ate involved in the bioactivation of several carcinogens, and phase II enzymes that take part in detoxification by conjugatiion the electrophilic compounds formed by the phaxe I enzymes with small bio-molecules (e.g. glutathione). Hence, the toxicological outcome of exposure, absorption and activation/detoxfication of xenobiotes depends on a delicate balance between the phase I and II enzymes. Polymorphism at genes encoding these enzymes can thus result in altered metabolism and result in toxicity or mutagenicity thereby altering individual susceptibility to diseases caused by environmental agents. Many studies have been conducted on the potential association between polymorphic expression of CYP1A1, CYP2D6, GSTM1, GSTM3, GSTP1, GSTT1 and various types of environmentally induced cancers, particularly those that are related to tobaccl abuse. CYP1A1, CYP2D6 and CYP2E1 polymorphic alleles have been associated with susceptibility to lung, and head and neck cancers. Apart from modulating head and aneck cancer risk, polymouphisms at GSTM1, GSTM3,GSTP1 and GSTT1 gene loci have also been involved in a variety of tobaccl associated cancers like lung, bladder and oesophageal cancer. The relationship between polymorphisms at metabolic gene loci and cancer risk is known to vary in distinct ethnic groups. This suggests that the variant alleles can not serve as universal biomarkers o susceptibility to environmental carcinogens. Studies on polymorphism at CYP and GST gene loci that have identified host factors responsible for modifying susceptibility to tobaccl-related cancers are documented in this review

Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population

This study evaluates the influence of genetic polymorphism at GSTM1, GSTM3 and GSTT1 gene loci on oral cancer risk among Indians habituated to the use of, smokeless tobacco, bidi or cigarette. DNA extracted from white blood cells of 297 cancer patients and 450 healthy controls by the proteinase K phenol-chloroform extraction procedure were analyzed by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) analyses. Lifetime tobacco exposure was evaluated as a risk factor in relation to the polymorphism at the GST gene loci using logistic regression analysis. There was no significant difference in the distribution of the GSTM3 and GSTT1 genotypes between oral cancer patients and controls. In contrast, a significant 3-fold increase in risk was seen for patients with the GSTM1 null genotype (age adjusted OR = 3.2, 95% CI 2.4-4.3). The impact of the GSTM1 null genotype on oral cancer risk was also analyzed in separate groups of individuals with different tobacco habits. The odds ratio associated with the GSTM1 null genotype was 3.7 (95% CI 2.0-7.1) in tobacco chewers, 3.7 (5% CI 1.3-7.9) in bidi smokers and 5.7 (95% CI 2.0-16.3) in cigarette smokers. Furthermore, increased lifetime exposure to chewing tobacco appeared to be associated with a 2-fold increase in oral cancer risk in GSTM1 null individuals. The results suggest that the GSTM1 null genotype is a risk factor for development of oral cancer among Indian tobacco habitues

Polymorphism at GSTM1 and CYP2D6 gene loci and modulation of oral cancer risk

In this study, the link between polymorphisms at GSTMI and CYP2D6 gene loci and individual susceptibility to oral cancer was analysed using blood samples from 150 patients with cancer of the buccal mucosa and 200 controls matched for age and sex. DNA extracted from white blood cells was subjected to polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis for detection of GSTM1 and CYP2D6 genotypes. The percentage of GSTM1 null individuals was significantly higher in oral cancer patients than in controls (42% vs 23%; p<0.001, odds ratio 2.11, 95% C.I 1.34 - 3.33). Comparative analysis of the CYP2D6 intron 3 - exon 4 polymorphism revealed that the frequencies of the homozygous normal (+/+), heterozygous (+/-), and homozygous mutant (-/-) genotypes were similar in oral cancer patients and controls. However, in combinational analysis the frequency of the GSTM1 null and CYP2D6 +/+ genotype was found to be higher in the cancer patients than in controls (38% vs 16%). The findings shown that individuals with the GSTM1 null allele and those with the combined GSTM1 null and CYP2D6 +/+ genotype are at a higher risk of developing tobacco related oral cancer

Biological monitoring of bidi industry workers occupationally exposed to tobacco

Ambient and biological monitoring was undertaken among tobacco processors who are chronically exposed to tobacco particulates via nasopharyngeal and cutaneous routes. Ambient monitoring revealed that the inspirable dust concentration was 150-fold higher in the tobacco factory than in the control environment, and was associated with chronic bronchitis in workers. Increased systemic exposure to tobacco constituents was evident from the high levels of cotinine, thioethers, promutagens and direct acting mutagens in workers' urine. The mean glutathione level and glutathione S-transferase activity were significantly lower in the peripheral blood lymphocytes of workers; however, the frequency of the GSTM1 null allele was similar to that in controls. A significant increase in chromosomal damage was noted in target and non-target cells of tobacco processors. In view of the association between tobacco use and several non-communicable diseases, the findings of the present study indicate an urgent need to minimize tobacco exposure among the processors

Influence of smokeless tobacco exposure on detoxification status and chromosomal damage in male and female habitues

In India, a large number of tobacco chewers and masheri users are chronically exposed to tobacco genotoxicants. Detoxification processes involving cellular glutathione (GSH) and glutathione S-transferases (GST) determine the outcome of exposure to environmental mutagens including those present in tobacco. Hence, in this study, GSH levels, GST activity, GSTM1 genotype and cytogenetic damage were determined using lymphocytes from 114 smokeless tobacco habitues and controls. The study groups comprised of male tobacco chewers, female masheri users, and age- and sex-matched controls. Irrespective of the tobacco habit, GSH levels and GST activity were higher in females than in males. In both the groups of habitues, GSH levels were similar to those in controls, while a significant reduction in GST activity was observed in tobacco chewers only. The frequency of cytogenetic alterations was significantly elevated in both the groups of habitues with respect to controls. However, break-type aberrations were more frequent in tobacco chewers while gaps were commonly observed in masheri users. Differences in the nature of chromosomal alterations in the two groups of habitues appeared to be related to variation in total tobacco exposure and gender-related differences in the efficacy of the GSH/GST detoxification system

Polymorphisms in NAT2 and GSTP1 are associated with survival in oral and oropharyngeal cancer

IntroductionFunctional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC).MethodsOOSCC cases (N=159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan-Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups.ResultsKaplan-Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P=0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10-0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0.54-2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31-1.59) (P-for-NAT2/treatment-interaction=0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P=0.04) but this association was not modified by treatment.ConclusionsOur results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required